Method for ensuring resuspension of paliperidone palmitate preparations

Abstract

This provides a strategy for ensuring the necessary resuspension of paliperidone palmitate. [Solution] A method is provided for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, for reducing the force required to inject the sustained-release injectable suspension of paliperidone palmitate, or for reducing the possibility of incomplete injection of the sustained-release injectable suspension of paliperidone palmitate, the method comprising maintaining the syringe in a desired orientation different from the orientation of the syringe during pre-shipment storage during shipment. 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 has undergone pre-shipment storage and shipment, and the syringe has been maintained in an orientation different from the orientation of the syringe during pre-shipment storage during shipment.

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) The present disclosure relates to methods for 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 schizotypal disorders. 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. Palmitic acid paliperidone is a palmitic acid ester of paliperidone (9 - hydroxy - risperidone), a monoamine - acting antagonist that exhibits the characteristic dopamine type 2 (D

[0004] and serotonin (5 - hydroxytryptamine type 2A) antagonism of second - generation atypical antipsychotics. Paliperidone (9 - OH risperidone) is the main active 2(D 2) metabolite of risperidone. ​It is a sexual metabolite. It is a sustained-release (ER) osmotically controlled release orally. c Control Release Oral Delivery (OROS) Paliperidone is administered as a tablet, integrated into the body. It is marketed in the United States for the treatment and maintenance of the effects of various illnesses.

[0005] Paliperidone palmitate is an antipsychotic drug used to treat schizophrenia and other related conditions that are usually treated with antipsychotics. Developed as a long-acting, intramuscular (im) injectable aqueous nanosuspension for the treatment of related diseases. It is emitted. Due to its very low water solubility, paliperidone compounds such as paliperidone palmitate are used. Stel is hydrolyzed to paliperidone, which slowly dissolves after intramuscular injection before circulating in the systemic circulation. It will become available in [location].

[0006] Monthly injections of paliperidone palmitate provide sustained plasma concentrations of paliperidone. It is developed to do so, which can greatly improve administration compliance. Aqueous nano-suspension Paliperidone palmitate, formulated as a turbidity solution, is protected by U.S. Patent No. 6,077,843. These are described in and in Patent Nos. 6,555,544, which are referred to herein by reference, respectively. It will be incorporated into the drug regimen of paliperidone palmitate to treat the patient. The patent is disclosed in U.S. Patent No. 9,439,906 and No. 10,143,693. These are incorporated herein by reference, respectively.

[0007] Paliperidone is currently available for therapeutic use in the following three formulations: Oral Sustained-release formulation (INVEGA® Extended Release (ER) tablets, I NVEGA (registered trademark), also known as prolonged-release (PR) tablets. , and two long-acting injectable (LAI) formulations (palmith Paliperidone phosphate 1-month injection [INVEGA SUSTENNA® or XE] PLION (registered trademark) and paliperidone palmitate 3-month injection type [INVEGA TRINZA (registered trademark) or TREVICTA (registered trademark)). Administered once every six months. Another palmitate paliperidone product intended for the same purpose (paliperidone palmitate 6-month injection) ) aims to further improve adherence and convenience, and has adopted the [INVEGA] in the United States. Approved in HAFYERA (trademark) and Europe (BYANNLI (trademark)).

[0008] Paliperidone palmitate suspension formulations are typically highly concentrated products. As a result... An important consideration is to ensure complete suspension / resuspension of the product before administration. To minimize the overall opportunity for administration, a healthcare professional will administer the medication, both during preparation and administration. It is necessary to follow specific guidelines. For example, INVEGA TRINZA ( The (registered trademark) label indicates that the syringe containing the formulation should be used to ensure a homogeneous suspension. It is clearly stated that you should shake it vigorously for at least 15 seconds beforehand (instructions for use (inst (corresponding to injections for use, IFU). Also, inject slowly, for example, 20-30 This must be done over a period of seconds. Shake the syringe while the tip is facing upwards. It is also recommended that the label for INVEGA HAFYERA (trademark) contains the formulation. Shake the syringe very quickly for at least 15 seconds (with the syringe tip cap facing upwards). It should be specified that it should be shaken for 15 seconds again after that, followed by a short pause, and then shaken again for 15 seconds. It is stated.

Summary of the Invention

Problems to be Solved by the Invention

[0009] Due to insufficient resuspension and resulting human errors that can cause incomplete administration of the palmitic acid paliperidone suspension, there may be several examples of deviation from the resuspension protocol. There is a need for further strategies to ensure the necessary resuspension of palmitic acid paliperidone. There may be a possibility that there are some examples of deviating from the resuspension protocol due to insufficient resuspension and resulting human errors that can cause incomplete administration of the palmitic acid paliperidone suspension. There is a need for further strategies to ensure the necessary resuspension of palmitic acid paliperidone.

Means for Solving the Problems

[0010] A method for improving the resuspensibility of a sustained-release injectable suspension of palmitic acid paliperidone in a syringe, which includes maintaining the syringe in a substantially horizontal orientation during shipment of the syringe, is provided herein. Also, a method for improving the resuspensibility of a sustained-release injectable suspension of palmitic acid paliperidone in a syringe, which includes maintaining the syringe in an orientation different from the orientation of the syringe in the storage tube before shipment during shipment, for example, in a substantially horizontal orientation during shipment of the syringe if the orientation during storage before shipment was not substantially horizontal, is provided herein. A method for improving the resuspensibility of a sustained-release injectable suspension of palmitic acid paliperidone in a syringe, which includes maintaining the syringe in a substantially horizontal orientation during shipment of the syringe, is provided herein. A method for improving the resuspensibility of a sustained-release injectable suspension of palmitic acid paliperidone in a syringe, which includes maintaining the syringe in an orientation different from the orientation of the syringe in the storage tube before shipment during shipment, for example, in a substantially horizontal orientation during shipment of the syringe if the orientation during storage before shipment was not substantially horizontal, is provided herein. A method for improving the resuspensibility of a sustained-release injectable suspension of palmitic acid paliperidone in a syringe, which includes maintaining the syringe in an orientation different from the orientation of the syringe in the storage tube before shipment during shipment, for example, in a substantially horizontal orientation during shipment of the syringe if the orientation during storage before shipment was not substantially horizontal, is provided herein. A method for improving the resuspensibility of a sustained-release injectable suspension of palmitic acid paliperidone in a syringe, which includes maintaining the syringe in an orientation different from the orientation of the syringe in the storage tube before shipment during shipment, for example, in a substantially horizontal orientation during shipment of the syringe if the orientation during storage before shipment was not substantially horizontal, is provided herein. A method for improving the resuspensibility of a sustained-release injectable suspension of palmitic acid paliperidone in a syringe, which includes maintaining the syringe in an orientation different from the orientation of the syringe in the storage tube before shipment during shipment, for example, in a substantially horizontal orientation during shipment of the syringe if the orientation during storage before shipment was not substantially horizontal, is provided herein.

[0011] Also, a method for reducing the force required for injecting a sustained-release injectable suspension of palmitic acid paliperidone from a syringe, which includes maintaining the syringe in a substantially horizontal orientation during shipment of the syringe, is disclosed. Also, a method for reducing the force required for injecting a sustained-release injectable suspension of palmitic acid paliperidone from a syringe, which includes maintaining the syringe in a substantially horizontal orientation during shipment of the syringe, is disclosed. A method for reducing the force required for injecting a sustained-release injectable suspension of palmitic acid paliperidone from a syringe, which includes maintaining the syringe in a substantially horizontal orientation during shipment of the syringe, is disclosed. A method for reducing the force required for injecting a sustained-release injectable suspension of palmitic acid paliperidone from a syringe, which includes maintaining the syringe in a substantially horizontal orientation during shipment of the syringe, is disclosed. ​A method for reducing the force required for the injection of a peridone sustained-release injectable suspension, The syringes inside the package are facing a different orientation than the one they were facing during pre-shipment storage, for example, the orientation they were facing during pre-shipment storage. If the syringe is not substantially horizontal, during shipment the syringe will be in a substantially horizontal orientation. Methods for maintaining are disclosed.

[0012] This disclosure also relates to the non-consumption of paliperidone palmitate sustained-release injectable suspension from syringes. A method to reduce the possibility of complete injection, and during the shipment of the syringe, the syringe is substantially The present disclosure relates to a method including maintaining a horizontal orientation. A method to reduce the possibility of incomplete injection of paliperidone mitinate sustained-release injectable suspension. Therefore, during shipment, the syringe may be oriented in a different direction than the one it was in storage before shipment, for example, before shipment. If the orientation during storage was not substantially horizontal, the syringe should be shipped in a substantially horizontal orientation. This relates to methods, including maintaining the syringe.

[0013] Furthermore, the resuspension properties of the paliperidone palmitate sustained-release injectable suspension in the syringe were improved. A method to improve the situation is to keep the syringe in a substantially horizontal position during storage. A method is provided that includes the following: A method for improving the resuspensionability of a release-injectable suspension, during shipment, during pre-shipment storage. The syringe is oriented in a different direction than its intended orientation, for example, if its orientation during pre-shipment storage is not substantially horizontal. This includes maintaining the syringe in a substantially horizontal position during storage if necessary. A method is provided.

[0014] Also, syringes containing paliperidone palmitate sustained-release injectable suspension. It is a collection of syringes, and each syringe is shipped to its destination, and the syringe is a syringe During shipment, the assembly of syringes, each maintained in a substantially horizontal orientation, is disclosed. Also, syringes containing a sustained-release injectable suspension of paliperidone palmitate. It is an assembly of syringes, each of which is shipped to its destination, and during shipment, pre-shipment storage The orientation of the syringe inside is different from that of the syringe, for example, the orientation during pre-shipment storage is not substantially horizontal. If not, the syringes will be kept in a virtually horizontal position during shipment. Then, the syringe assembly is revealed.

[0015] This disclosure also relates to palmitic cells in syringes for administration to patients suffering from schizophrenia. A pharmaceutical product containing a sustained-release injectable suspension of paliperidone phosphate, the syringe is shipped The syringe has undergone pre-storage and is being shipped, but its orientation is different from that of the syringe during pre-storage. We provide pharmaceutical products that are maintained in their orientation during shipment.

[0016] Furthermore, a method for treating schizophrenia, in which a patient suffering from schizophrenia is given a palmistry treatment. The procedure involves administering a sustained-release injectable suspension of paliperidone zinate from a syringe. The syringe has undergone pre-shipment storage and has been shipped, and the orientation of the syringe during pre-shipment storage. A method is disclosed in which the shipment was maintained in a different orientation. Also, the treatment of schizophrenia A sustained-release injectable suspension of paliperidone palmitate for use in the method These methods involve administering paliperidone palmitate to patients suffering from schizophrenia. The process involves administering a continuous-release injectable suspension from a syringe, provided the syringe has undergone pre-shipment storage. However, the syringes were shipped in a different orientation than the syringes were in during storage before shipment. A sustained-release injectable suspension of paliperidone palmitate, which was maintained within it, is disclosed. Furthermore, the sustained-release paliperidone palmitate in the manufacture of pharmaceuticals for treating schizophrenia The use of an injectable suspension, wherein the paliperidone palmitate sustained-release injectable suspension is Prepared for administration from a syringe, the syringe undergoes pre-shipment storage and is shipped. Furthermore, if the syringe is maintained in a different orientation during shipment than the orientation it was in during storage before shipment, Furthermore, the use will be disclosed.

[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, palmitate The lidone sustained-release injectable suspension is PP3M. In one embodiment, parsyl palmitate is used. The peridone sustained-release injectable suspension 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] This figure shows the injection power profiles for process performance qualified (PPQ) batches of PP6M stored in one of five different spatial orientations. [Figure 1D]This figure shows the injection power profiles for process performance qualified (PPQ) batches of PP6M stored in one of five different spatial orientations. [Figure 1E] This figure shows the injection power profiles for process performance qualified (PPQ) batches of PP6M stored in one of five different spatial orientations. [Figure 1F] This figure shows the injection power profiles for process performance qualified (PPQ) batches of PP6M stored in one of five different spatial orientations. [Figure 2A] This figure shows the injection force curve for syringes subjected to vibration experiments while in a horizontal or tip-down orientation. [Figure 2B] This figure shows the injection force curve for syringes subjected to vibration experiments while in a horizontal or tip-down orientation. [Figure 2C] This figure shows the injection force curve for syringes subjected to vibration experiments while in a horizontal or tip-down orientation. [Figure 2D] This figure shows the injection force curve for syringes subjected to vibration experiments while in a horizontal or tip-down orientation. [Modes for carrying out the invention]

[0019] The subject matter of the present invention disclosed herein relates to the accompanying drawings, which form part of this disclosure. You can understand this more easily by referring to the detailed explanation provided below. The present invention relates to specific formulations, methods, conditions or parameters described and / or indicated herein. Not limited to the above, the technical terms used herein will be explained using examples. This is solely for the purpose of describing embodiments and does not limit the claimed invention. It should be understood that this was not the intended effect.

[0020] The entire disclosures of each patent, patent application, and publication cited or referenced herein are subject to the terms of this specification. This is incorporated herein by reference.

[0021] When used above, and throughout this disclosure, the following terms and abbreviations are, in particular, as indicated above. Unless otherwise specified, please understand that it has the following meaning.

[0022] In this disclosure, unless otherwise specified, the singular forms "a," "an," and "the" are used in the plural form. A reference to a shape is inclusive, and a reference to a specific number is inclusive, at least, of that specific value. For example, a reference to "a formulation" may be one or more such... This is a reference to eel preparations and their equivalents known to those skilled in the art. Furthermore, certain elements When indicating that X, Y, or Z "may" be used, such use is in all cases This is not intended to exclude other options regarding that element.

[0023] When a value is expressed as an approximation using the antecedent "approximately", that particular value is an approximation of another implementation. It is understood that the form is formed. Generally, the use of the term "about" indicates the disclosing inventor. This shows an approximate value that may vary depending on the desired characteristic being sought in the problem, and its function Based on this, it should be interpreted in the specific context in which it is used. In terms of form, "approximately X" (where X is a numerical value) broadly refers to ±10% of the stated value. For example The phrase "approximately 8" can broadly refer to values ​​between 7.2 and 8.8. This value is It may include "exactly 8". If present, all ranges are inclusive and combinational. Yes, it is possible. For example, when listing the range "1 to 5", the listed range can be arbitrarily selected as "1 Ranges such as "~4", "1~3", "1~2", "1~2 and 4~5", "1~3 and 5", etc. It should be interpreted as including. In addition, if a list of alternatives is clearly provided, such The list may also include embodiments in which any of the substitutes may be excluded. For example, "1 If a range of "~5" is specified, such a specification means that any of 1, 2, 3, 4, or 5 It is possible to support a situation in which any of them are excluded. Therefore, the description "1-5" means It could be argued that the answer is "1 and 3-5, but not 2," or simply "2 is not included."

[0024] One or more compounds or formulations thereof (e.g., paliperidone palmitate sustained-release) This specification concerns treatment methods (for example, methods for treating schizophrenia) that use injectable suspensions. The references in the book are, - For example, one or more compounds for use in a method of treating schizophrenia or preparations thereof (e.g., paliperidone palmitate sustained-release injectable suspension), and / or teeth - For example, the formulation of a medicine in the manufacture of a medicine for treating schizophrenia (for example, palmitic Reference to the use of one or more compounds of paliperidone phosphate sustained-release injectable suspension. It should be understood that this should also be interpreted in that way.

[0025] As mentioned above, to ensure complete administration of the paliperidone palmitate injectable suspension Therefore, a resuspension protocol exists. The prescribed paliperidone palmitate preparation is administered... The precise procedure for preparing the formulation for the drug, and the manner in which the injection itself should be administered. Although it includes clear label instructions, paliperidone palmitate should only be administered by healthcare professionals following specific procedures. Ensure sufficient resuspension, thereby delivering the prescribed dosage to the patient as needed. There's a possibility that it won't be done in a way that ensures it will be done.

[0026] The inventors of this application have surprisingly found a syringe containing a suspension of palmitate paliperidone. The orientation of the syringe should be changed during the shipping process from the orientation of the syringe during the pre-shipment storage period. However, it was found that this affects the resuspension properties of the drug product in the preparation for administration. In particular, The syringe is oriented differently from its orientation during pre-shipment storage, for example, substantially horizontally during shipment. Maintaining the syringe in this way means, for example, that the syringe is stored with the tip facing downwards even before shipment. In contrast to the conventional downward-facing orientation during shipping, when this occurs, palmitate palmitate This improves the resuspendability of peridone, thereby ensuring complete administration of the prescribed dosage. It was found that the possibility is improved. Therefore, this discovery is due to human error or pal A formulated resuspension device intended to ensure sufficient resuspension of paliperidone mitinate. Mitigating other causes of deviation from Rotor (e.g., managing the type and duration of shaking) It has the effect of improving drug resuspension, resulting in a reduction in the amount of force required for administration, etc. Specific benefits are obtained, and as a general problem, the opportunity for incomplete administration is reduced. By reducing the shaking force required for resuspension, the resuspension process can be improved. It is also possible that the opportunity for incomplete administration is reduced, and consequently, the patient is able to receive the intended treatment. This also means that the risks of taking a lower dose of paliperidone palmitate than the recommended dose are reduced. This means that if the prescribed resuspension protocol is deviated from, for example, during shipment, or in a different orientation from the orientation of the syringe during storage before shipment, for example, substantially horizontal orientation during shipment. From the syringe that has been maintained, administer the paliperidone palmitate sustained-release injectable suspension. Patients suffering from schizophrenia, for example, during shipping, the conventional tip-down orientation Administer paliperidone palmitate sustained-release injectable suspension from a syringe maintained at [location / device]. Patients who are not receiving treatment are less likely to take a dose lower than the intended dose. This means that, for example, during shipping, the orientation of the syringe may differ from the orientation of the syringe during storage before shipping. The syringe is maintained in an orientation, for example, substantially horizontal during shipping, when the pulp is released from the syringe. The administration of paliperidone zinate sustained-release injectable suspension has made an important contribution to the field of schizophrenia therapy. To express devotion.

[0027] Therefore, resuspension of the paliperidone palmitate sustained-release injectable suspension in the syringe. A method for improving quality, wherein during the shipment of the syringe, the syringe is positioned in a substantially horizontal orientation. Methods including maintaining in a syringe are provided herein. The disclosure also provides methods including from a syringe For those who want to reduce the possibility of incomplete injection of paliperidone lumitate sustained-release injectable suspension. A law that includes maintaining the syringe in a substantially horizontal position during shipment. This includes methods such as a sustained-release injectable suspension of paliperidone palmitate in a syringe. A method for improving the resuspension properties of a liquid, wherein the orientation of the syringe during pre-shipment storage is... In a different orientation, for example, if the orientation during storage before shipment was not substantially horizontal, The method described herein includes maintaining the syringe in a substantially horizontal orientation during the shipment of the syringe. Provided by [company name]. This disclosure also allows for sustained-release injection of paliperidone palmitate from a syringe. A method to reduce the possibility of incomplete injection of a nasal suspension during shipment, during pre-shipment storage. The syringe may be oriented in a different direction than intended, for example, if its orientation during pre-shipment storage is not substantially horizontal. In such cases, the syringe must be kept in a substantially horizontal position during shipment, including the following: It includes methods.

[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, palmitate The lidone sustained-release injectable suspension is PP3M. In one embodiment, parsyl palmitate is used. The peridone sustained-release injectable suspension is PP6M.

[0029] Paliperidone ester contains a racemic mixture of (+)- and (-)-paliperidone. These are antipsychotic drugs belonging to the chemical classification of benzisoxazole derivatives, and they are used in the United States. This is described in Japanese Patent No. 5,254,556 (which is 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 - It is illhexadecanoate. The structural formula is as follows:

[0030] [ka]

[0031] Paliperidone ester is a US-made product, both of which are incorporated herein by reference. As described in Permission Nos. 5,254,556 and 6,077,843, pharmaceutical dispensations The formulation can be made into an injectable dosage form. The injectable formulation can be formulated in an aqueous carrier. ru.

[0032] Paliperidone palmitate sustained-release injectable suspension can be administered, for example, once every three months for six months. This may include commercially available formulations intended to be administered to the target once or at any other interval. stomach.

[0033] A commercially available formulation intended for administration once every three months is INVEGA TRIN. Examples include ZA (registered trademark) or TREVICTA (registered trademark). Incorporated by reference. See also U.S. Patent No. 10,143,693. In this disclosure, “PP3M” means Palmitate paliperidone, which contains an amount of palmitate suitable for a dosing interval of approximately 3 months. This refers to peridone sustained-release injectable suspension or other types of formulations. For example, "PP3M" is This refers to a sustained-release injectable suspension of paliperidone palmitate with a dosing interval of approximately 3 months. It is possible.

[0034] In the United States, INVEGA is a commercially available formulation intended for administration once every six months. HAFYERA (trademark) is one example. A formulation for administration once every six months is available from BYANN. It has received marketing approval in Europe under the product name LI (registered trademark). In this disclosure, "P "P6M" contains a dose of paliperidone palmitate suitable for a dosing interval of approximately 6 months. This refers to paliperidone mitinate sustained-release injectable suspension or other types of formulations. For example, "P P6M is a sustained-release injectable paliperidone palmitate with a dosing interval of approximately 6 months. It can refer to a turbid liquid. PP6M is typically about 1000 mg to 1600 mg. It is supplied in a range of doses of paliperidone palmitate, with a 6-month dosing interval. Provides a sustained therapeutic concentration of peridone. Preferably, PP6M is about 1092 mg or about The drug product is supplied with a dose strength of 1560 mg of paliperidone palmitate. It is hydrolyzed to paliperidone, which is approximately 700 mg equivalent or 1000 mg equivalent, respectively. This provides the dose intensity of paliperidone.

[0035] PP6M is preferably 700 mg equivalent (3.5 mL) or 1000 mg equivalent (5 mL). Paliperidone (0 mL) (1092 mg or 1560 mg of paliperidone palmitate, respectively) One of the following pre-filled plunger stoppers, plunger rods (as Lidon): and tip cap (bromobutyl rubber), backstop, and needle, preferably thin-walled 20 Pre-filled syringe with a 1.5-inch safety needle of gauge (G) (cyclic olefin copolymer) It will be provided at ).

[0036] PP3M is typically a palmitate compound in doses ranging from approximately 270 mg to approximately 825 mg. It is supplied as liperidone, and a sustained therapeutic concentration of paliperidone is administered over a 3-month interval. Provided. Preferably, PP3M is provided in a quantity of approximately 273, 410, 546, or 819 mg. The drug product is supplied with paliperidone mitinate in dose strength. The active part of the drug is paliperidone mitinate. It is hydrolyzed into approximately 175, 263, 350, or 525 mg equivalents of paripelago, respectively. The dose intensity of Don is obtained.

[0037] PP3M is preferably pre-filled with approximately 175 mg equivalent to approximately 525 mg equivalent. Runja stopper, plunger rod, and tip cap (bromobutyl rubber), back Stop and needle, preferably a thin-walled 20 gauge (G) 1.5-inch safety needle, or a thin-walled 2 Pre-filled syringe with 2 gauge (G) 1-inch safety needle (cyclic olefin copolymer) It will be provided at [location / service name].

[0038] In certain embodiments, PP3M and PP6M may have the same formulation, and each The total volume of the suspension preparation contained in the syringe differs according to this method. The amount of paliperidone palmitate suspension used is approximately 250 to 1600 mg in absolute terms. It may contain paliperidone palmitate. The amount of paliperidone palmitate in the suspension is For example, it may be 273, 410, 546, or 819 mg. In certain embodiments, The amount of paliperidone palmitate in the turbid solution may be 1092 or 1560 mg.

[0039] In certain embodiments, the 3-month (PP3M) formulation has an average particle size of less than approximately 20 μm to approximately 1 μm. It has a diameter. In other embodiments, the particles are about 5 μm to about 15 μm, and about 3 μm to about 10 μm. , or have an average particle size (d50) of approximately 5 μm to approximately 9 μm. d90 is approximately 50 μm, approximately 1 It can be 0 μm to approximately 30 μm, or approximately 10 μm to approximately 20 μm. d10 is approximately 1 μm to approximately It can be 10 μm, or approximately 1 μm to 5 μm.

[0040] In certain embodiments, the 6-month (PP6M) formulation has a particle size of less than approximately 30 μm to approximately 1 μm, or approximately The average particle size is 20 μm to about 1 μm. In other embodiments, the particles are about 3 μm to about 25 The average particle size is μm, approximately 5μm to 15μm, approximately 3μm to 10μm, or approximately 5μm to 9μm. It has a diameter (d50). d90 is approximately 60 μm, or approximately 50 μm, or approximately 10 μm to approximately 30 μm. m, or approximately 10 μm to approximately 20 μm. d10 is approximately 1 μm to approximately 15 μm, approximately 1 μ The size can be approximately 10 μm or approximately 1 μm to 5 μm.

[0041] When used herein, this refers to sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. When measured by prior art known in the relevant field, such as distance, d10: Smaller than this value The proportion of particles with a diameter of 10% is d50: particles with a diameter smaller than this value. The proportion of particles is 50%. d90: The proportion of particles with a diameter smaller than this value is 90%. It is a percentage.

[0042] Suitable aqueous nanoparticle formulations are described in U.S. Patent No. 6,555,544, see reference This is incorporated herein by means of. In some embodiments, the formulation is microparticles, interface A group consisting of activators, suspending agents, and optionally preservatives, buffering agents, and isotonic agents. It contains one or more additional ingredients.

[0043] Surface modifiers useful for paliperidone palmitate preparations physically adhere to the surface of the active drug. However, it is thought that it includes substances that do not chemically bond. Suitable surface modifiers are known A variety of excipients can be selected from organic and inorganic pharmaceutically acceptable excipients. Such excipients include various polymers, low It contains molecular weight oligomers, natural products, and surfactants. Suitable surface modifiers are nonionic and Contains anionic surfactants. Typical examples of excipients include gelatin, casein, and resin. Citin (phosphatide), acacia gum, cholesterol, tragacanth, stearic acid , benzalkonium chloride, calcium stearate, glyceryl monostearate, ceto Stearyl alcohol, cetomacrogol emulsified wax, sorbitan ester, polyoxyen ethylene alkyl ethers (for example, macrogol ethers such as cetomacrogol 1000) ), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (For example, commercially available TWEEN®), polyethylene glycol, polyoxyethylene Stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, calcium Calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose Lurose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl Ropil methylcellulose phthalate, amorphous cellulose, magnesium aluminosilicate , triethanolamine, polyvinyl alcohol (PVA), Poloxamer, tyroxapole, and polyvinylpyrrolidone (P VP) is one example. Most of these excipients are from American Pharmaceuticals. The Pharmaceutical Association and The Pharmaceutical Society Co-published by the City of Great Britain, The Hand book of Pharmaceutical Excipients, the Ph. Detailed information is available in Armaceutical Press, 1986. Surface modifiers These can be commercially available and / or prepared by techniques known in the art. Two or more surface modifiers may be used in combination.

[0044] Particularly preferred surface modifiers include polyvinylpyrrolidone; tyroxapol; poloxa For example, ethylene oxide and propylene oxide available from BASF PLURONIC® F68, F108 and F127, which are poroxine copolymers; Samines, for example, ethylene oxide and plutonium diamine available from BASF. TETR is a tetrafunctional block copolymer derived from the sequential addition of propyl oxide. ONIC (trademark) 908 (T908); Dextran; Lecithin; Cytec Indu Ae, a dioctyl ester of sodium sulfosuccinate, is available from Stries. Rosol OT (Trademark) (AOT); Sodium lauryl sulfate available from DuPont. Alcohol, a trademark of DUPONOL®, is available from Rohm and Haas. TRITON(trademark) X-200;ICI is a killaryl polyethersulfonate. Polyoxyethylene sorbite is available from Specialty Chemicals. TWEEN® 20, 40, 60, and 80 fatty acid esters; fatty acid s Rubitan esters SPAN(trademark) 20, 40, 60 and 80; Hercules ARLACEL® 2, a sorbitan ester of fatty acids available from , Inc. 0, 40, 60, and 80; polyethylene available from Union Carbide The recall is for CARBOWAX® trademarks 3550 and 934; Croda Inc. CRO is a mixture of sucrose stearate and sucrose distearate that is available from the market. DESTA (trademark) F110; available from Croda Inc. A(trademark) SL-40; Hexyldecyltrimethylammonium chloride (CTAC); Bovine serum albumin, and the following formula: C 18 H 17 CH2(CON(CH3)CH2(C SA90HCO, which contains HOH)4CH2OH)2, is an example. It has been found to be particularly useful. The surface modifiers used include tyroxapol and poloxamer, preferably Pluronic Includes (trademark) F108 and Pluronic(trademark) F68.

[0045] Pluronic(trademark) F108 corresponds to poloxamer 338, and is of formula HO[CH2 CH2O] x [CH(CH3)CH2O] y [CH2CH2O] z H(x, y, and z) Polyoxyethylene (whose average values ​​are 128, 54, and 128, respectively) is approximately in line with Polyoxypropylene block copolymer. Other commercially available poloxamer 338. The name is Hodag NONIONIC(trademark) 1108-F, available from Hodag. and SYNPERONIC® PE / F1 available from ICI Americas It is 08.

[0046] The optimal relative amounts of paliperidone palmitate and surface modifiers depend on various parameters. The optimal amount of surface modifier is, for example, the selected specific surface modifier, the surface modifier in micelles. The formation of these structures may depend on factors such as the critical micelle concentration of the surface modifier and the surface area of ​​the antipsychotic agent. The specific surface modifier is preferably paliperidone palmitate per square meter of surface area It is present in amounts of approximately 0.1 to 1 mg. Paliperidone palmitate (9-palmitic acid In the case of hydroxyrisperidone, as a surface modifier, PLURONIC (trademark) It is preferable to use F108, and a relative amount (w / w) of both components of approximately 6:1 is preferred. It is suitable.

[0047] The particles of the palmitate paliperidone suspension are dispersed in a liquid dispersion medium. The steps involve dispersing the particles and, in the presence of a grinding medium, adjusting the particle size of the antipsychotic to an effective average particle size. It can be prepared by a method including the step of applying mechanical means to reduce it to The particles can have their dimensions reduced in the presence of a surface modifier. Alternatively, the particles can be modified. After wear, it can come into contact with a surface modifier.

[0048] The general procedure for preparing particles of palmitate paliperidone suspension is as follows: (a) (b) obtain paliperidone palmitate and add paliperidone palmitate to a liquid medium. (c) forming a premix, and (c) mechanically grinding the premix in the presence of a grinding medium. This may include subjecting the material to a means to reduce it to an effective average particle size.

[0049] Paliperidone palmitate can be prepared using techniques known in the art. As determined by sieve analysis, the particle size of paliperidone palmitate is approximately 100 μm. It is preferable that the particle size of paliperidone palmitate exceeds approximately 100 μm. In this case, it is preferable to reduce the size of the paliperidone palmitate particles to less than 100 μm. It's nice.

[0050] Next, paliperidone palmitate is intrinsically insoluble in order to form a premix. It can be added to a certain liquid medium. The concentration of paliperidone palmitate in the liquid medium (by weight) Weight (by cent) can vary greatly, depending on the antipsychotic agent selected and the surface selected. It depends on the denaturing agent and other factors. The preferred concentration of paliperidone palmitate in the composition is The range is approximately 0.1 to 60%, preferably approximately 0.5 to 30%, and more preferably More specifically, it is approximately 7% (w / v). In the case of PP3M, approximately 200 mg equivalent per 1 mL. Use liperidone, or a concentration of paliperidone palmitate equivalent to approximately 312 mg per 1 mL. It is preferable to use paliperidone. In the case of PP6M, approximately 200 mg equivalent per 1 mL. Alternatively, use a concentration of paliperidone palmitate equivalent to approximately 312 mg per 1 mL. It is preferable.

[0051] Another exemplary procedure involves pre-processing the grain size before subjecting it to mechanical means to reduce the effective average grain size. Includes the addition of a surface modifier to the mix. Concentration of the surface modifier (by weight percentage). This can range from approximately 0.1% to approximately 90%, preferably from approximately 0.5% to approximately 80%, and more preferably The percentage is approximately 7% (w / v).

[0052] The premix is ​​used to reduce the effective average particle size within the dispersion to a desired particle size. It can be used directly by subjecting it to mechanical means. When a ball mill is used for wear, It is preferable to use the premix directly. Alternatively, an antipsychotic agent and, optionally, The surface modifier is mixed using, for example, a roller mill or coreless mixing method until homogeneous dispersion is achieved. It can be dispersed in a liquid medium using a suitable stirring device or similar.

[0053] Mechanical means applied to reduce the effective average particle size of antipsychotic drugs are, for convenience, divided It can take the form of a dispersion mill. Suitable dispersion mills include ball mills, grinding mills, vibratory mills, and planetary mills. This includes media mills such as mills, sand mills, and bead mills. Media mills reduce the particle size to a desired degree. This is preferable because the milling time required to produce a small amount is relatively short. Regarding the saturation, in some embodiments, the apparent viscosity of the premix is ​​preferably about It is 0.1 Pa·s to approximately 1 Pa·s. In some embodiments, ball milling is performed The apparent viscosity of the premix is ​​preferably about 1 mPa·s to about 100 mPa·s. be.

[0054] The grinding medium for the particle size reduction step is preferably less than about 3 mm, more preferably about 1 A hard medium in spherical or granular form with an average diameter of less than 1 mm can be selected. A medium such as the above can preferably provide the particles of the present invention in a shorter processing time. This can reduce wear on the grinding equipment. The selection of materials for the grinding medium is important. It is considered unimportant. However, magnesia, zirconium silicate, and glass Approximately 95% ZrO stabilized with a grinding medium provides particles acceptable for the preparation of pharmaceutical compositions. It also provides polymer beads, stainless steel, titania, alumina, and yttrium. Other media such as approximately 95% ZrO stabilized with 2. 5 g / cm 3 Having a density exceeding approximately 95, stabilized with magnesia and polymer beads. Contains %ZrO.

[0055] Wear time can vary greatly and depends mainly on the specific mechanical means and the selected processing conditions. It depends. Regarding rolling mills, for small particles, processing can take up to 2 days or longer. Processing time may be required.

[0056] The particles must decrease in size at a temperature that does not significantly decompose the antipsychotic drug. Approximately 30 A processing temperature of ℃ to less than approximately 40℃ is generally preferred. If necessary, the processing apparatus may be conventional. It can be cooled with a cooling device. The method is safe and effective under ambient temperature conditions and for grinding. It is executed conveniently due to processing pressure.

[0057] If a surface modifier is not present in the premix, it typically occurs after wear, for example, on The amount specified for the premix is ​​added to the dispersion. The dispersion is then, for example, The mixture can be mixed by vigorous shaking. Optionally, the dispersion can be mixed using, for example, ultrasonic power. It can be used in distributed processes by supplying it.

[0058] The aqueous composition contains a suspending agent and a buffering agent, and optionally one of a preservative and an isotonic agent. Or it may further contain two or more. Certain ingredients may be two or three or more of these drugs. They can function simultaneously, for example, acting as a preservative and a buffer, or as a buffer and It can act like an isotonic agent.

[0059] Suitable suspending agent (also called a physical stabilizer) for use in aqueous suspensions as described in the present invention (These are cellulose derivatives, for example, methylcellulose, carboxymethylcellulose) Sodium and hydroxypropyl methylcellulose, polyvinylpyrrolidone, argy Nate, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene These are ylene- and polyoxypropylene ethers. Preferably, carboxymethyl cellulose. Sodium cellulose is used at a concentration of approximately 0.5 to 2%, most preferably about 1% (w / v). It is used.

[0060] Preferred surfactants selected from those described for use in aqueous suspensions according to the present invention The humectant is a polyoxyethylene derivative of sorbitan ester, such as polysorbic acid. 20 and polysorbic acid 80, lecithin, polyoxyethylene-, and polyoxypropyl The polysorbic acid 20 is a lene ether and sodium deoxycholate. Preferably, polysorbic acid 20 is Approximately 0.5 to 3%, more preferably approximately 0.5 to 2%, most preferably approximately 1.1% It is used at a concentration of (w / v).

[0061] A suitable buffer is a salt of a weak acid, sufficient to make the dispersion pH from approximately 6.0 to basic. It should be used in a controlled amount. Preferably, the pH should be in the range of about 6.0 to about 9.0, or about 6. The range is approximately 0 to 8.0, or approximately 6.5 to 7.5. For example, pH is approximately 6.0 to 7.5. Within the range of 6.5, or approximately 6.5 to approximately 7.0, or approximately 7.0 to approximately 7.5, or approximately 7.5 to approximately 8.0, or approximately 8.0 to 8.5, or approximately 8.5 to 9.0. (Disodium hydrogen phosphate) Um (anhydrous) (typically about 0.9% (w / v)) and sodium dihydrogen phosphate monohydrate The use of a mixture of substances (typically about 0.6% (w / v)) is particularly preferred. This buffering agent This makes the dispersion isotonic and, in addition, reduces the tendency of the ester suspended therein to aggregate. .

[0062] The preservatives are benzoic acid, benzyl alcohol, butylated hydroxyanisole, and butylated Hydroxytoluene, chlorobutol, gallate, hydroxybenzoate, EDTA phenol, chlorocresol, metacresol, benzethonium chloride, myristyl- A group consisting of gamma-picolinium chloride, phenylacetate nitrate, and thimerosal. It can be selected from antibacterial and antioxidant agents. In particular, it can be up to approximately 2% (w / v), preferably at a maximum concentration of about 1.5% (w / v), benzyl aldehyde can be used. It's a call.

[0063] Isotonic agents include, for example, sodium chloride, dextrose, mannitol, sorbitol, The components are lactose and sodium sulfate. The suspension is conveniently isotonic, with a concentration of approximately 0% to 10% (w / v). Contains the agent. Mannitol can be used at a concentration of about 0% to about 7%, but more preferably, Probably to help prevent the aggregation of suspended esters, about 1% to about 3% ( (w / v), especially one or more electrolytes in a concentration of approximately 1.5% to 2% (w / v) in the suspension It is used to make a solution isotonic. In particular, the electrolyte in a buffer acts as an isotonic agent. .

[0064] A particularly desirable feature of injectable formulations relates to the ease with which they can be administered. In particular, Such injections are feasible to administer in the shortest possible time, using the thinnest possible needle. This must be done by using the aqueous suspension of the present invention and putting it into a syringe (for example, a vial) By maintaining a specific viscosity that allows it to be easily absorbed and injected through a fine needle... This can be achieved. For example, in some embodiments, the viscosity is approximately 75 mPa·s at room temperature. It is full or less than approximately 60 mPa·s. For PP3M, a 22G 1 and 1 / 2 inch needle. Alternatively, a 22G 1-inch needle is typically used. For PP6M, a 20G 1 and 1 / 2-inch needle is used. Inch needles are typically used.

[0065] Ideally, the aqueous suspension for use described in this method should be designed to minimize the injection volume. It contains a number of prodrugs that can be tolerated, and as few other ingredients as possible.

[0066] In particular, in the case of PP3M or PP6M, the composition is (a) approximately 200 to approximately 500 mg / mL (b) a prodrug, (c) a humectant of approximately 2 to 25 mg / mL, (b) approximately 2.5 to 50 mg / (d) one or more mL of buffering agent, (e) approximately 25 to approximately 150 mg / mL of suspending agent, )Optionally, up to approximately 2% (w / v) of preservatives, and (f) the remaining amount until it reaches 100% It may contain water, or may essentially consist of water. Typically, PP3M or The PP6M composition has a pH of about 6.0 to about 8.0, preferably about 6.5 to about 7.5. It has.

[0067] In other embodiments, for PP3M or PP6M, the composition is (a) about 250 to about 40 (b) 0 mg / mL prodrug, (c) approximately 5 to approximately 20 mg / mL humectant, (b) approximately 5 to approximately (d) One or more buffers at 25 mg / mL, (d) a suspension at approximately 50 to 100 mg / mL (e) a preservative, optionally, up to approximately 2% (w / v), and (f) until it reaches 100%. It may contain the remaining water, or may essentially consist of it.

[0068] In other embodiments, for PP3M or PP6M, the composition is (a) about 280 to about 35 (b) a prodrug of 0 mg / mL, (c) a humectant of approximately 8 to 12 mg / mL, (b) a humectant of approximately 5 to 12 mg / mL (d) One or more buffers of 15 mg / mL, (d) suspension of approximately 65 to 85 mg / mL (e) optional preservatives, up to approximately 2% (w / v), and (f) until 100% It may contain the remaining amount of water, or may essentially consist of it.

[0069] The active ingredient in PP3M or PP6M is paliperidone palmitate (approximately 312 mg / m²). Includes L). In certain preferred embodiments, the active ingredient in PP3M or PP6M is poly Solvate 20 (approx. 10 mg / mL), polyethylene glycol 4000 (approx. 75 mg / mL) mL), citric acid monohydrate (approximately 7.5 mg / mL), sodium dihydrogen phosphate monohydrate ( It is likely to be (approximately 6 mg / mL), sodium hydroxide (approximately 5.4 mg / mL), and sterile water for injection. The illustrated PP3M is disclosed in Example 1. The illustrated PP6M is disclosed in Example 2. It has been disclosed.

[0070] This method involves preparing a sustained-release injectable suspension of paliperidone palmitate during syringe shipment. This method also includes maintaining the syringe containing the product in a substantially horizontal position. Syringes containing paliperidone sustained-release injectable suspension are stored during shipment. The orientation of the syringe inside is different from that of the syringe, for example, the orientation during pre-shipment storage is not substantially horizontal. This includes, if not present, maintaining the syringe in a substantially horizontal position during storage.

[0071] Regardless of the specific orientation of the syringe during pre-shipment storage, according to this method, Changing the orientation of syringes during shipment after pre-shipment storage is approximately 45 degrees from the orientation during storage. This could mean maintaining the syringe in the shipping direction, representing an angular deviation of approximately 135°. The orientation of the syringes during shipping is approximately 45, 50, and 55 degrees different from the orientation of the syringes stored before shipping. , 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, It can vary by 115, 120, 125, 130, or 135°.

[0072] For example, the orientation of the syringe during shipping may be substantially horizontal. This is particularly suitable when the syringe was stored with its tip facing upward or downward. The "tip" of a syringe refers to the part of the syringe to which the needle is attached for injection purposes. A substantially horizontal orientation means that the syringe is perpendicular to the ground relative to gravity, or the syringe is shipped The orientation is such that the angle is closer to 0° than 90° with respect to an applicable reference point such as the floor of the vehicle. It can point to. For example, a substantially horizontal orientation is 0, 2, 3, 4, 5 relative to the relevant reference point. , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 2 0, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3, Directions that are 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44° It could refer to...

[0073] In other embodiments, the orientation of the syringe during shipping may be substantially tip-up. This is because the syringe was oriented with the tip facing downwards or substantially horizontally during pre-shipment storage. This indicates the correct shipping orientation in the event of a problem. The tip-up orientation means the syringe tip is facing gravity. In contrast, with respect to an applicable reference point such as a vertical ground or the floor of the vehicle on which the syringe is shipped, 0 It can refer to an angle closer to 90° than a degree. For example, an upward-pointing tip is related to 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80 relative to the reference point ,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, 5 It can refer to directions of 3, 52, 51, 50, 49, 48, 47, or 46°.

[0074] In other embodiments, the orientation of the syringe during shipping may be substantially tip-down. This is because the syringe was oriented with the tip facing upward or substantially horizontal during storage before shipment. This indicates the correct shipping orientation when the syringe is in the specified orientation. This could refer to a direction that is 180° inverted to one of the upward-pointing directions of the tip.

[0075] Regardless of the specific orientation during shipping, "maintaining" the orientation means, preferably, an acceptable orientation. This means the angle is applied for most of the time during the shipping process. Ideally, during shipping If a substantially horizontal orientation is desired, the syringe will always be at an angle perpendicular to gravity during shipping. Although it is maintained each time, in practice, due to changes in the orientation of the vehicle in which the syringe is shipped Therefore, changes in orientation inevitably occur during shipping. For example, the orientation of the syringe may change for shipping. When the truck carrying the gasoline is stationary on flat terrain, it is perpendicular to gravity. However, this orientation changes when trucks go up and down hills during the shipping process. Therefore, a useful reference point may be the floor of the vehicle being shipped, rather than gravity. Furthermore, the syringe is maintained in an orientation that is substantially parallel to the floor of the vehicle during shipment.

[0076] Maintaining a specific orientation during shipment ensures that the syringe is placed in the shipping vehicle in the desired orientation. Loading, monitoring the syringes during shipment to ensure they maintain the desired orientation, or so This may include both. Loading the syringe into the shipping vehicle in the desired orientation, the package The orientation of the product when it is placed on the transport vehicle is intended not to be intentionally changed during the shipping process. This refers to the method of positioning the syringe package in the shipping vehicle during shipment. Monitoring the syringe to ensure it maintains the desired orientation is a human effort to ensure adherence to the desired orientation. Direct or indirect observation by an automated system programmed to verify, Or may include a combination of these. Direct observation by a person is prohibited when the packaging containing the syringe is closed. This may include visual inspection by a person. Indirect observation may involve the syringe and the packaging containing the syringe. A sensor that can be attached to the page or both, or another method that enables its monitoring. This may include the use of objects. The sensor may relate, for example, to the orientation of a syringe and / or package. It can acquire information and transmit it to a human observer, and the human observer can then access the transmitted information. However, it is necessary to determine whether the syringe is maintained in the required orientation during the shipping process. The sensor also detects if the orientation of the container or package deviates from the correct orientation, for example. For example, if the container / package moves during shipping, an alarm or some other notification will be issued. It is also possible to transmit. In one embodiment, a particular orientation, or a desired orientation, is substantially It is horizontal.

[0077] A human monitor or sensor that can detect information regarding the orientation of a syringe is a syringe It may be possible to provide a direct determination of the orientation of the syringe, or the packaging that houses the syringe. This can be done indirectly by determining the orientation of the package. The markings on the outside of the syringe visually indicate the corresponding orientation of the syringe stored within the package. The target clue can be provided to a sensor or human monitor. Therefore, the syringe is It may be stored in a container (package) including the outer surface, and the outer surface may be in place during shipping. Maintain the container in an orientation corresponding to the desired syringe orientation (e.g., substantially horizontal orientation). It has an explanation or marking that enables it. In some embodiments, the explanation is of the syringe Depending on the origin of the shipment, the personnel handling the shipment, and the destination of the syringe, it will be provided in the appropriate language. Obtain. In some embodiments, markings on the outer surface of the container are made appropriately, the container This may also be an arrow indicating whether the side of the throat should be facing upwards, downwards, or to the side. Alternatively, if markings are observed, the syringe contained in the container shall be correct according to this method. To be turned towards.

[0078] Syringes are shipped by airships (airplanes, helicopters, etc.), trucks, boats, trains, etc. By any necessary means of transport, or at the time of shipment from the drug manufacturing facility to the medical facility where the drug will be administered. This can be done by any combination of these means that can be carried out from a point. Total duration of shipment Time is required to transport the syringe from its initial storage location to a second location, such as a medical facility. It can be any period as needed. For example, the duration of shipment could be approximately 1, 2, 3, 4, 5, 6, 7 It may take 8, 9, 10, 11, 12, 13, 14, or 15 hours. The shipping process is This may include the period while the syringe is being transported, for example, before any further transport intervals. This involves one or more intervals in a temporary storage location during which the syringes are not being transported. For the purposes of this disclosure, the duration of shipment is defined as the time from the initial storage facility after manufacturing when transporting the syringes. This refers to the total amount of time that elapses from the point of discharge until arrival at the facility where the administration is performed. It's possible, but it doesn't necessarily have to be.

[0079] This method involves storing the syringe in a designated location after shipment and before administration of the drug suspension. And further includes maintaining in a deliberately selected orientation, for example, substantially horizontal orientation. Obtain. From this perspective, the floor of the storage facility is horizontal and thereby perpendicular to gravity. Because of the high probability, a substantially horizontal orientation is preferably substantially parallel to the floor of the storage facility. This can refer to the angle between the long axis of the syringe and the floor of the storage facility. The degree is preferably about 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than 1° It could mean something.

[0080] As described above, this method facilitates the resuspension of the contents of the paliperidone palmitate syringe. And improve. One intended result of resuspending paliperidone palmitate particles. This represents a reduction in the residue of unresuspended paliperidone palmitate within the syringe tip. It is either small or removed. Resuspension is incomplete to some extent, and the palmitate palmitate is not resuspended. Lipiridone may remain in the tip of the syringe after administration, thereby affecting delivery. This indicates the drug that has not been administered and is an indicator of incomplete administration. It represents the resuspension remaining in the syringe tip after administration. Minimizing the amount of residue representing paliperidone palmitate, which has not been removed, is essential. Further beneficial results of the method disclosed in the details are shown. For example, according to this method, syringe tip The end represents approximately 3, 2.5, 2, 3, 2, 3, 2, 3, 4, 3, 4, 3, 4, 3, 4, 3, 4, 4, 3, 4, 4, 4, 4, 5 It may contain residues of 1.5, 1, or 0.5 mm or less. In some embodiments, The tip of the syringe represents approximately 3,2.8 units of paliperidone palmitate that has not been resuspended after administration. , 2.6, 2.5, 2.4, 2.2, 2.1, 2, 1.9, 1.8, 1.7, 1.6, 1 0.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5 It contains residues of 0.4, 0.3, 0.2, 0.1, or 0 mm.

[0081] The syringe may be of any type, and may be a paliperidone palmitate injection syringe. It may be equipped with any needle suitable for storing and administering the turbid fluid. For example, the syringe may have 1, 1 0.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 2.8, 3, 3.2 5, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5. It may have a volume of 75, 6, 6.25, 6.5, 6.75, or 7 mL. Several implementations In terms of form, the syringe has a capacity of 1, 2.25, 2.8, or 3 mL and a length of 1 or 1 Includes a 22 gauge needle that is 0.5 inches in diameter. In some embodiments, the syringe contains 5 mL Includes a 20-gauge needle having capacity and a length of 1.5 inches. In either case, the volume of a syringe-injectable suspension of paliperidone palmitate. 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. The volume may be 25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, or 7 mL.

[0082] This method involves a suspension from a syringe (i.e., one that was maintained in the desired orientation during shipping). The procedure may further include the step of administering the agent to the patient. In some embodiments, the desired orientation is actually The quality is horizontal. The administration of the suspension is, for example, the commercially available paliperidone palmitate mentioned above. This should be done according to the protocol outlined on the label of the sustained-release injectable suspension product. Yes. This method is used before and during administration of paliperidone palmitate sustained-release injectable suspension. While strictly adhering to the recommended steps reduces specific instances of failure by healthcare professionals, Therefore, administration of the suspension from the syringe using this method ensures compliance with the labeling protocol. Still desirable.

[0083] At the same time, this method ensures that the syringe is kept in a substantially horizontal position during shipment. This allows for a reduction in the force required for injection of paliperidone palmitate sustained-release injectable suspension. Therefore, this disclosure relates to the injection of paliperidone palmitate sustained-release injectable suspension. It includes methods to reduce the force required for injection. For example, the force required for injection from a syringe. The force is from the syringe, which was not kept in a substantially horizontal orientation during shipment. The required injection strength of paliperidone zinate sustained-release injectable suspension is approximately 5% to 60% less. It's not necessary. The force required for injection from a syringe is, for example, substantially water during the release of the syringe. Sustained-release injection of paliperidone palmitate is possible from a syringe that is not kept flat. The force required for injecting the suspension is approximately 5, 10, 15, 20, 25, 30, 35, 40, 45. It may be 50, 55, or 60% smaller. In some embodiments, the injection from the syringe The force required for injection is whether the syringe was not kept in a substantially horizontal position during shipment. The required force for injection of paliperidone palmitate sustained-release injectable suspension is approximately 10 times less than the required force. It can be 55, 15-50, 20-50, 25-45, or 30-40% smaller. In addition At the same time, this method ensures that during shipment, the syringe is oriented in a different direction than the one it was in storage before shipment, for example. If the orientation of the syringe during storage before shipment is not substantially horizontal, the syringe will be substantially horizontal during shipment. Paliperidone palmitate can be administered by sustained-release injection from a syringe held horizontally. This disclosure allows for a reduction in the force required for injection of the suspension. Therefore, this disclosure relates to par palmitate. This invention includes methods for reducing the force required for the injection of a sustained-release peridone injectable suspension. For example, the force required for injection from a syringe may differ from the orientation of the syringe during storage before shipment. Sustained-release injection of paliperidone palmitate is possible from syringes that were not maintained in the correct orientation during transport. The force required for injection of the suspension may be approximately 5-60% less than the force needed for injection from a syringe. The necessary force is, for example, not maintained in a different orientation during shipment than in the orientation of the syringe during storage before shipment. The required amount for injection of paliperidone palmitate sustained-release injectable suspension from a syringe Approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 6 times the force. It may be 0% smaller. In some embodiments, the force required for injection from the syringe is shipped Syringes that were not maintained in a different orientation during shipping than the orientation during previous storage may cause problems. The required force for injection of paliperidone lumitate sustained-release injectable suspension is approximately 10-55 times stronger. It can be 15-50, 20-50, 25-45, or 30-40% smaller.

[0084] From an absolute standpoint, the sustained-release injectable suspension of paliperidone palmitate from a syringe The force required for injection is not maintained in a substantially horizontal position during the syringe's shipment. Approximately 10 times the force required for injection of paliperidone palmitate sustained-release injectable suspension. ~25 Newtons is also acceptable. The force required for injection from a syringe is, for example, the force of a syringe Palmitate pariperi from syringes that were not kept in a substantially horizontal orientation during shipment. The force required for injection of Don's sustained-release injectable suspension is approximately 10, 11, 12, 13, 14. 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 Newtons (small) It may be cut. Injection of paliperidone palmitate sustained-release injectable suspension from a syringe. The amount of force actually required could be, for example, about 10 to 25 Newtons. Therefore, The force required for injection from a syringe is, for example, about 10, 11, 12, 13, 14, 15, 16 It could be 17, 18, 19, 20, 21, 22, 23, 24, or 25 Newtons. In addition, from an absolute standpoint, paliperidone palmitate can be administered by sustained-release injection from a syringe. The force required for injecting the turbidity is maintained in a different orientation during shipping than the orientation of the syringe during storage before shipping. Injection of paliperidone palmitate sustained-release injectable suspension from a syringe that was not used. The force required for injection from a syringe can be about 5 to 25 Newtons less than necessary. For example, syringes that were not maintained in a different orientation during shipping than the orientation they were in during storage before shipping. The force required for injecting a sustained-release paliperidone palmitate injectable suspension from a syringe is greater than Approximately 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, or 25 Newtons, which may be smaller. From a syringe The amount of force actually required for the injection of paliperidone palmitate sustained-release injectable suspension is, for example, Therefore, the force required for injection from a syringe is approximately 10 to 25 Newtons. For example, approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 2 It could be 1, 22, 23, 24, or 25 Newtons.

[0085] This method involves injecting a sustained-release injectable suspension of paliperidone palmitate from a syringe. This may further include assessing the amount of force required to complete the task. The assessment may be based on any available This can be done using measurement techniques.

[0086] This method also involves or, paliperidone palmitate sustained-release injection from a syringe. This may include evaluating whether the injection of the possible suspension has been completed. The evaluation may include, for example, Lengths approximately 4, 3.75, 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, 1.7 Values ​​exceeding specific values ​​such as 5, 1.5, 1.25, 1, 0.75, 0.5, or 0.25 mm. To measure the amount of unresuspended paliperidone palmitate in the tip of the syringe It may include.

[0087] Furthermore, the resuspension properties of the paliperidone palmitate sustained-release injectable suspension in the syringe were improved. A method to improve the situation is to keep the syringe in a substantially horizontal position during storage. Methods including the following are disclosed herein: Storage of syringes before shipment of syringes Alternatively, this may be done later. In certain embodiments, the storage of the syringes may be after the syringes have been shipped, for example. For example, this is done at a medical facility that administers paliperidone palmitate. Our method improves resuspension, including maintaining the syringe in a substantially horizontal position during shipment. This can be implemented independently of or in combination with the above-mentioned methods. In other words, The syringe may be stored in a substantially horizontal position, and may be shipped in a substantially horizontal position. Shipment and storage may often be carried out in a horizontal or substantially horizontal orientation. The correct orientation for storing syringes should be indicated by markings or other instructions on the packaging or container that holds the syringes. This may be facilitated by a light, and such markings will be substantially horizontal during shipping. The markings or descriptions intended to ensure the maintenance of the markings may be the same as, or different from, those intended to ensure the maintenance of the markings. It may be maintained. Similar to the case of a method including maintaining a substantially horizontal orientation during shipment The method may further include monitoring to ensure maintaining a substantially horizontal orientation during storage. The approach for monitoring may be the same as that described in relation to maintaining a substantially horizontal orientation during shipment. Also, a method for improving the resuspensibility of a sustained release injectable suspension of paliperidone palmitate in a syringe, during shipment, in an orientation different from the orientation of the syringe during pre-shipment storage, for example, when the orientation during pre-shipment storage is not substantially horizontal, maintaining the syringe in a substantially horizontal orientation during storage of the syringe is disclosed herein. The storage of the syringe may be performed before or after shipment of the syringe. In certain embodiments, the storage of the syringe is performed after shipment of the syringe, for example, at a location corresponding to a medical facility where administration of paliperidone palmitate is to be performed. These methods may be performed independently of or in combination with the above-described method for improving resuspensibility, including maintaining the syringe in an orientation different from the orientation of the syringe during pre-shipment storage during shipment. That is, the syringe may be shipped in a substantially horizontal orientation and then stored in a substantially horizontal orientation, may be shipped in a substantially horizontal orientation, or may be shipped and stored in a substantially horizontal orientation. The storage of the syringe in a particular orientation may be facilitated by markings or other instructions on the package or container that houses the syringe, and such markings may be the same as or different from markings or instructions intended to ensure maintaining the desired orientation during shipment. Similar to the case of a method including maintaining a particular orientation during shipment, the method ensures maintaining the desired orientation during storage. These methods may be performed independently of or in combination with the above-described method for improving resuspensibility, including maintaining the syringe in an orientation different from the orientation of the syringe during pre-shipment storage during shipment. It may be shipped and stored in a substantially horizontal orientation. That is, the syringe may be shipped in a substantially horizontal orientation and then stored in a substantially horizontal orientation, may be shipped in a substantially horizontal orientation, or may be shipped and stored in a substantially horizontal orientation. The storage of the syringe in a particular orientation may be facilitated by markings or other instructions on the package or container that houses the syringe, and such markings may be the same as or different from markings or instructions intended to ensure maintaining the desired orientation during shipment. Similar to the case of a method including maintaining a particular orientation during shipment, the method ensures maintaining the desired orientation during storage. The storage of the syringe in a particular orientation may be facilitated by markings or other instructions on the package or container that houses the syringe, and such markings may be the same as or different from markings or instructions intended to ensure maintaining the desired orientation during shipment. Such markings may be markings or instructions intended to ensure maintaining the desired orientation during shipment, or may be the same as or different from the instructions. Similar to the case of a method including maintaining a particular orientation during shipment, the method ensures maintaining the desired orientation during storage. for the purpose of ensuring. This may further include monitoring the desired orientation during shipping. An approach to monitoring is to maintain the desired orientation during shipping. The same as those mentioned above in relation to holding may also be acceptable.

[0088] This disclosure also contains, respectively, a sustained-release injectable suspension of paliperidone palmitate. It is an assembly of syringes, and each syringe is shipped to its destination, and the syringes are During the shipment of syringes, the syringe assemblies were maintained, each in a substantially horizontal orientation. Provides improved resuspension after administration. Therefore, each member of the syringe assembly has improved resuspension properties. This includes less residue in the syringe tip, less force required for administration, etc., and is essentially horizontal. The aforementioned benefits are obtained by shipping in a certain orientation. The syringe assembly is approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 8 0, 85, 90, 95, 100, 120, 140, 160, 180, 200, 225, 2 50, 275, 300, 325, 350, 375, 400, 425, 450, 475, 5 00, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1 400, 1500, 1600, 1700, 1800, 1900, 2000 pieces, or 200 It may contain more than zero individual syringes. Each member of the syringe assembly is specified herein. Syringe-type and palmitate palipe This disclosure may include a lidone suspension. In addition, this disclosure also includes a sustained-release injection of paliperidone palmitate. An assembly of syringes, each containing an injectable suspension, wherein each syringe is intended to reach the target They are shipped, and during shipping, the syringes may be oriented in a different direction than when they were stored before shipping, for example. If the orientation of the syringe during storage before shipment is not substantially horizontal, the syringe will be substantially water-resistant during shipment. This provides a collection of syringes, each syringe held in a flat orientation. Each member of the syringe assembly has improved resuspension, and the contents of the syringe tip after administration This includes less residue, less force needed for administration, etc., during shipment, and during storage before shipment. The aforementioned benefits are obtained by shipping in a direction different from the orientation of the syringe. Syringe assembly The numbers are approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, and 65. , 70, 75, 80, 85, 90, 95, 100, 120, 140, 160, 180, 2 00, 225, 250, 275, 300, 325, 350, 375, 400, 425, 4 50, 475, 500, 600, 700, 800, 900, 1000, 1100, 120 0, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 200 May contain 0 or more individual syringes. Each member of the syringe assembly - Syringe type and P It may contain a suspension of paliperidone lumitate.

[0089] Additionally, the syringe contains palmitate palmitate for administration to patients suffering from schizophrenia. A pharmaceutical product containing a peridone sustained-release injectable suspension, wherein the syringe is stored before shipment. The syringes are received and shipped, but they come out facing a different orientation than the syringes were in during storage before shipment. The pharmaceutical product maintained in the package is provided herein. Paliperidone palmitate Continuous-release injectable suspension, syringe, pre-shipment storage conditions, syringe orientation during pre-shipment storage, The characteristics of the shipping conditions and the orientation of the syringe during shipping are related to the palmitic acid inside the syringe. The method of the present invention for improving the resuspensibility of a pariperidone sustained-release injectable suspension, and the syringe assembly of the present invention may follow any of the above-described embodiments in combination. .

[0090] [[ID=⑧]]<OOO0961> For example, the syringe may be housed in a container including an outer surface, and the outer surface includes an explanation for maintaining the container during shipment in a direction corresponding to the desired direction of the syringe. In some embodiments, 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. After shipment, the syringe may contain a residue of about 1.5 mm or less or about 1 mm or less representing palmitic acid pariperidone that has not been resuspended after injection of the suspension. For example, the syringe may contain a residue of about 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 palmitic acid pariperidone that has not been resuspended after injection of the suspension.

[0091] The pariperidone palmitate sustained-release injectable suspension in the syringe may contain about 2,73, 410, 546, or 819 mg of pariperidone palmitate. In other embodiments, the suspension contains about 1,092 or 1,560 mg of pariperidone palmitate. 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. The orientation during shipment may vary from about 45° to about 135° from the orientation of the syringe during storage before shipment.

[0092] For example, the orientation of the syringe during shipment may be about 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, or 130° from the orientation of the syringe during storage before shipment. 115, 120, 125,又は130°変化し得る。

[0093] The orientation during shipment may vary from about 45° to about 135° from the orientation of the syringe during storage before shipment. For example, the orientation of the syringe during shipment may be about 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, or 130° from the orientation of the syringe during storage before shipment. It can vary by 0, 115, 120, 125, 130, or 135°.

[0094] In some embodiments of the pharmaceutical products disclosed herein, the orientation for pre-shipment storage is, The end was facing downward. In some embodiments of the pharmaceutical products disclosed herein, the shipment The orientation was substantially horizontal. In certain embodiments of the pharmaceutical products disclosed herein, The orientation for storage before shipment was with the tip facing downwards, and the orientation for shipment was with the tip facing upwards, or substantially It was horizontal. In other embodiments, the orientation for pre-shipment storage was tip-down, and The orientation of the load was substantially horizontal. In other embodiments, pre-shipment storage was with the tip facing downwards. Furthermore, the shipping direction was with the tip facing upwards.

[0095] This disclosure also relates to a method for treating schizophrenia, which is used in patients suffering from schizophrenia. This includes administering a sustained-release injectable suspension of paliperidone palmitate from a syringe. The syringes have undergone pre-shipment storage and have been shipped, and the syringes are in pre-shipment storage. This disclosure provides a method for maintaining a different orientation during shipment than the orientation of the product. Paliperidone palmitate sustained-release injection for use in the treatment of phallus. Possible suspensions, these methods for administering palmitic acid to patients suffering from schizophrenia The procedure involves administering a paliperidone sustained-release injectable suspension from a syringe, wherein the syringe is The syringes have undergone pre-shipment storage and have been shipped, but their orientation is different from that of the syringes during pre-shipment storage. A sustained-release injectable suspension of paliperidone palmitate, which was maintained in the correct orientation during shipment. The administration of the suspension is, for example, the commercially available paliperidone palmitate sustained-release formulation mentioned above. This should be done according to the protocol outlined on the label of the injectable suspension product. This method is recommended before and during administration of paliperidone palmitate sustained-release injectable suspension. While it reduces specific cases of failure by healthcare professionals who strictly adhere to the prescribed steps, this method The administration of suspensions from syringes by law still requires adherence to labeling protocols. It is desirable to do so.

[0096] Regarding currently disclosed methods for treating schizophrenia, paliperidone palmitate Continuous-release injectable suspension, syringe, pre-shipment storage conditions, syringe orientation during pre-shipment storage, dispensing The characteristics of the shipping conditions and the orientation of the syringe during shipment are related to the palmitate in the syringe. The present invention relates to a method for improving the resuspensionability of a sustained-release injectable liperidone suspension, and the present invention In combination with the syringe assembly of Akira, any of the embodiments described above may be followed.

[0097] For example, the syringe may be housed in a container that includes an outer surface, and the outer surface is silicone It included instructions on how to maintain the container in the orientation corresponding to the desired orientation of the lamp during shipping. In some embodiments, the syringe is housed in a container that includes an outer surface, and the outer surface is the syringe It included markings indicating the orientation of the container to maintain the desired orientation of the bottle.

[0098] After shipment, the syringe contains palmitate paliperid that has not been resuspended after injection of the suspension. It may contain residues of approximately 1.5 mm or less, or approximately 1 mm or less, representing the substance. For example, a syringe Approximately 1.5, 1.5, representing paliperidone palmitate that has not been resuspended after injection of the suspension. 4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0. It may contain residues of 4, 0.3, 0.2, or 0.1 mm.

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

[0100] The orientation of the syringes during shipping may vary by approximately 45° to 135° from the orientation of the syringes during storage before shipping. For example, the orientation of syringes during shipment differs by approximately 45 to 50 degrees from the orientation of syringes stored before shipment. 55, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 11 It can vary by 0, 115, 120, 125, 130, or 135°.

[0101] In some embodiments of the methods disclosed herein for treating schizophrenia, pre-shipment care The orientation of the tube was with the tip pointing downward. The method disclosed herein for treating schizophrenia In some embodiments, the shipping orientation was substantially horizontal. In certain embodiments of the law, the orientation for pre-shipment storage was tip-down, and the orientation for shipment was , with the tip facing upward or substantially horizontal. In other embodiments, the orientation for pre-shipment storage was tip-first. It was facing downwards, and the shipping orientation was substantially horizontal. In other embodiments, before shipping The product was stored with the tip facing downwards, while it was shipped with the tip facing upwards.

[0102] This disclosure also relates to the manufacture of pharmacopoei palmitate for the treatment of schizophrenia. Use of a sustained-release injectable suspension, paliperidone palmitate sustained-release injectable The suspension is prepared for administration from a syringe, and the syringe undergoes pre-shipment storage. The syringes were shipped in a different orientation than the one they were in during storage before shipment. Provided for use. The administration of the suspension is, for example, the above-mentioned commercially available palmitate palmitate. Follow the protocol outlined on the label of the liperidone sustained-release injectable suspension product. This should be done. This use involves the administration of paliperidone palmitate sustained-release injectable suspension. Specific examples of failures by healthcare professionals who strictly adhered to recommended pre- and post-administration steps. This reduces the risk, but administering the suspension from the syringe using this method may violate the labeling protocol. It is still desirable to abide by it.

[0103] Regarding the currently disclosed uses, paliperidone palmitate sustained-release injectable suspension Syringe, pre-shipment storage conditions, orientation of syringe during pre-shipment storage, shipping conditions, and during shipping The characteristics of each syringe orientation are related to the sustained-release injection of paliperidone palmitate within the syringe. Method of the present invention for improving the resuspensionability of an injectable suspension, and syringe assembly of the present invention. In combination with the above, any of the embodiments described above may be followed.

[0104] For example, the syringe may be housed in a container that includes an outer surface, and the outer surface is silicone It included instructions on how to maintain the container in the orientation corresponding to the desired orientation of the lamp during shipping. In some embodiments, the syringe is housed in a container that includes an outer surface, and the outer surface is the syringe It included markings indicating the orientation of the container to maintain the desired orientation of the bottle.

[0105] After shipment, the syringe contains palmitate paliperid that has not been resuspended after injection of the suspension. It may contain residues of approximately 1.5 mm or less, or approximately 1 mm or less, representing the substance. For example, a syringe Approximately 1.5, 1.5, representing paliperidone palmitate that has not been resuspended after injection of the suspension. 4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0. It may contain residues of 4, 0.3, 0.2, or 0.1 mm.

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

[0107] The orientation of the syringes during shipping may vary by approximately 45° to 135° from the orientation of the syringes during storage before shipping. For example, the orientation of syringes during shipment differs by approximately 45 to 50 degrees from the orientation of syringes stored before shipment. 55, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 11 It can vary by 0, 115, 120, 125, 130, or 135°.

[0108] In some embodiments of use disclosed herein, the orientation for pre-shipment storage is tip-down. In some embodiments of use disclosed herein, the direction of shipment is substantially It was horizontal. In certain embodiments of use disclosed herein, the orientation of pre-shipment storage The tip was facing downwards, and the shipping orientation was with the tip facing upwards, or substantially horizontal. In other embodiments, the orientation for pre-shipment storage was tip-down, and the shipping orientation was substantially It was horizontal. In other embodiments, pre-shipment storage was tip-down, and shipping The tip was pointing upwards.

[0109] The present invention is further defined with reference to the following numbered clauses. 1. Improve the resuspension properties of the paliperidone palmitate sustained-release injectable suspension in the syringe. A method to improve the situation is to keep the syringe in a substantially horizontal position during shipment. A method that includes doing something. 2. Maintaining the syringe in a substantially horizontal position ensures that the syringe is effectively placed in the shipping vehicle. Load them horizontally, monitor the syringes during shipping to maintain a substantially horizontal orientation. The method described in paragraph 1, which includes confirming or both. 3. Further comprising housing the syringe in a container including an outer surface, wherein the outer surface is substantially Instructions are provided to maintain the container in the direction corresponding to the orientation of the syringe, which is horizontal. The method described in item 1 or item 2. 4. Further comprising housing the syringe in a container including an outer surface, wherein the outer surface is substantially A marking indicating the orientation of the container to maintain the syringe orientation horizontally. The method described in any one of items 1 to 3. 5. After shipping the syringes, store them in a storage location in a substantially horizontal position. The method described in any one of items 1 to 4, further comprising doing the following. 6. Syringes are shipped by airplane, truck, boat, or rail, item 1~ The method described in any one of the five methods. 7. After shipment, the syringe contains paliperidone palmitate that has not been resuspended after administration. The method according to any one of items 1 to 6, which contains residue of approximately 1.5 mm or less that represents [the specified substance]. 8. After shipment, the syringe contains approximately paliperidone palmitate that has not been resuspended. The method according to any one of items 1 to 7, which contains residue of 1 mm or less. 9. The syringe has a capacity of 1 mL, 2.25 mL, 2.8 mL, or 3 mL, and The method according to any one of items 1 to 8, including a 22 gauge needle that is 1 or 1.5 inches long. . 10. The syringe has a capacity of 5 mL and contains a 20 gauge needle that is 1.5 inches long. The method described in any one of items 1 to 13. 11. The suspension contains approximately 273, 410, 546, or 819 mg of palmitate. The method according to any one of items 1 to 15, comprising lidon. 12. The suspension contains approximately 1092 or 1560 mg of paliperidone palmitate. The method described in any one of items 1 to 15. 13. Any of items 1 to 17, further comprising administering the suspension to the patient from a syringe. One method. 14. For injection of paliperidone palmitate sustained-release injectable suspension from a syringe. A method to reduce the force required, such as when the syringe is shipped, by keeping the syringe substantially horizontal. A method that includes maintaining the orientation. 15. The force required for injection from the syringe is not substantially horizontal during the shipment of the syringe. Paliperidone palmitate sustained-release injectable suspension from a syringe that was not maintained. The method described in item 23, which is approximately 20% to 50% less than the force required for the injection. 16. The force required for injection from the syringe is not substantially horizontal during the shipment of the syringe. Paliperidone palmitate sustained-release injectable suspension from a syringe that was not maintained. The method described in item 23 or 24, which is about 10 to 25 Newtons less than the force required for injection. . 17. The force required for injection from a syringe is approximately 10-25 Newtons, item 23- The method described in any one of the 25 methods. 18. Complete the injection of the paliperidone palmitate sustained-release injectable suspension from the syringe. Further including assessing the force required to complete the task, as described in any one of paragraphs 23-26. method. 19. Incomplete release of paliperidone palmitate injectable suspension from syringe. A method to reduce the possibility of injection, and during the shipment of syringes, the syringe is substantially... A method that includes maintaining a horizontal orientation. 20. The injection of paliperidone palmitate sustained-release injectable suspension from the syringe is complete. The method described in paragraph 28, further comprising evaluating whether it has been completed. 21. The resuspension properties of the paliperidone palmitate sustained-release injectable suspension in the syringe. A method for improvement, which involves maintaining the syringe in a substantially horizontal position during storage. A method that includes holding something. 22. The method described in paragraph 21, wherein the storage described above is carried out after the syringe has been shipped. 23. Syringes each containing a sustained-release injectable suspension of paliperidone palmitate. It is a collection of syringes, and each syringe is shipped to its destination, and the syringe is a syringe A collection of syringes, each 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 represent preferred embodiments of the present invention. While indicating the nature of the claim, it is given solely as an explanation and does not limit the scope of the attached claims. It should be understood that this should not be interpreted in that way. From the above considerations and these examples Those skilled in the art will be able to identify the essential features of the present invention and will not deviate from its spirit and scope. Without making any changes or modifications to the present invention, the present invention can be adapted to various uses and conditions. It can be made possible. Unless otherwise specified, references to PP6M in the examples are examples. This refers to the formulation described in point 2.

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

[0112] [Table 1]

[0113] PP3M can be supplied in pre-filled syringes, with dosage strengths ranging from 175 mg equivalent to 5 The range is 25 mg equivalent, and the syringe contains different volumes of 200 mg / mL equivalent bulk suspension. It can be obtained by filling with turbidity. Table 2 shows syringe size and nominal fill size. It shows different drug intensities, including volume.

[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 lists 200 mg / mL equivalents of palmitate suitable for intramuscular (IM) injection. This includes an exemplary 6-month sustained-release formulation of peridone (PP6M).

[0118] [Table 4]

[0119] PP6M can be supplied in pre-filled syringes, with dosage strengths ranging from 700 mg equivalent to 1 The range is 000 mg equivalent, and different volumes of 200 mg / mL equivalent bulk are placed in the syringe. It can be obtained by filling with a suspension. Table 5 shows the syringe size and nominal capacity. It shows different dosing intensities, including the volume of filling.

[0120] [Table 5]

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

[0122] [Table 6]

[0123] Example 3 - Storage conditions before shipment Stability testing was performed in five different orientations before shipment (horizontal, tip downward +45°, tip upward - At 45°, +45° with the tip pointing downwards, and -45° with the tip pointing downwards, the process performance of PP6M The tests were conducted using performance-qualified (PPQ) batches. The following test results were obtained from post-manufacturing storage. However, the results were obtained for syringes that were not shipped before the test. Shaking for 5 seconds resulted in... The experiment was conducted at two different temperatures (25°C and 30°C). The results from this experiment are shown in Table 7. To provide.

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

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

[0126] The results showed that products stored in any location before shipment could be resuspended with a normal amount of force. This means that the force required to expel the contents of the syringe is not present before shipment. This suggested that it was not related to the storage location. Different storage locations gave equivalent results, and this This means that if the syringe is stored in a location where it has been shaken for at least 5 seconds before shipment, it will be damaged. This indicates that it is not necessary. A complete injection could be performed with an acceptable injection force.

[0127] Following this experiment, the storage location of the product during stability testing and before shipment proved to be a crucial determinant of resuspendability. It became clear that it was not a child. As described in Example 4 below, the shipping direction is, It turned out to be far more important than the orientation of the storage location before shipment.

[0128] Example 4 - Orientation during simulated shipment After a storage period in the manufacturing facility with the tip facing downwards, syringes containing the PP6M formulation are used. Level I and Level R as defined by ASTM D4169-16 for simulated aerial shipments These were used in simulated shipping experiments using vibrations corresponding to those of the Bell II. This is the highest level of vibration, exceeding the vibration levels defined for truck shipments. To increase the sensitivity of the test for detecting the difference, resuspension of the PP6M formulation after simulated shipment. The properties and injectability can be checked by shaking without shaking, or by shaking for only 5 seconds (instructions for use). Shorter than defined by ions for use (IFU), INVEGA TRINZA (Registered Regarding the registered trademark (PP3M product), the description provided on the label matches that of PP6M. For IFU, it is 2 x 15 seconds of shaking, and for PP3M, it is 1 x 15 seconds The shaking test was performed. The residue remaining in the syringe and the syringe were emptied to that point. Table 8 below provides a summary of the maximum force required to do so.

[0129] [Table 8]

[0130] Figures 2A to 2D show the results of vibration experiments on syringes while they were horizontal or with their tips facing downwards. The resulting firing force curve is shown. Using the sensor on the thumb pad of the plunger rod, manually An injection feasibility test was performed by injection, and the force (Newtons) over time (seconds) was recorded. The vibration conditions followed ASTM D4169, with a 2-hour Level II simulated aerial shipment and a 3-hour It included a simulated aerial shipment at Level I. Figure 2A shows the tip facing downwards. This corresponds to syringes that have been shaken before injection. Figure 2B shows the tip pointing downwards. This corresponds to a syringe that is suitable for the user and has been shaken for 5 seconds before injection. Figure 2C This corresponds to a syringe that was in a horizontal position and was not shaken before injection. Figure 2D shows the syringe in a horizontal orientation, and the syringe had been shaken for 5 seconds before injection. Corresponds to the range.

[0131] The results from this experiment show that the syringe in the tip-down position after storage in the tip-down position... Depending on the type of syringe used, it may be necessary to apply very little force to squeeze out the contents. This means that the contents of such a syringe are not completely resuspended after shaking for 5 seconds. Confirm. In practice, healthcare providers should, especially when injecting patients, use 30N or 35 You don't need to press N.

[0132] However, if the syringe is stored with the tip facing downwards and then shipped in a horizontal position... In that case, the ejection force was in the range of 10 to 20 Newtons, so this means that the product This indicates that less shaking is required to achieve a good suspension. In comparison, Crab-based formulations with low concentration (therefore, their vulnerability to collisions is considerably lower, and therefore, re A 1-month injectable suspension of paliperidone palmitate (representing a preparation with even lower suspension requirements). The force required to release the liquid is in the range of 7 to 12 Newtons.

[0133] Example 5 - When the orientation of the syringe during shipment is changed from the orientation during storage before shipment, the injection The force and post-injection residue are reduced. The horizontal orientation of PP6M syringes during shipping has been improved compared to the downward-pointing orientation. Following the initial demonstration that it provides resuspension and injectability properties, different types and durations We will more deeply assess the potential impact of the interim shipment and the PP6M system up to 3 months after the simulated shipment. Further research was initiated to monitor the behavior of the syringe.

[0134] For this study, PP6M in a 5 mL syringe was selected from the stability chamber. Due to the higher product load in the mL syringe, the worst-case scenario for resuspension is 3. I selected the 5mL filler, not the 5mL filler.

[0135] Although stored in a stability chamber in different orientations before being exposed to simulated shipping conditions, Samples from different batches that have not yet been subjected to shipping conditions should be shaken insufficiently for 5 seconds. The resuspension / injectability was tested by manually injecting the syringe into the container. The injection force was recorded by a sensor attached to the thumb pad, and the residual product in the syringe was measured. The amount was measured. All samples were either free of product residue in the syringe or had an acceptable amount. A complete injection with product residue is performed, and different pre-shipment storage orientation settings are set, but itself Without affecting the properties of the suspension, the product can be easily resuspended after 9 months of storage. It was concluded that it was possible to administer it by injection.

[0136] Following this initial trial, the syringes were transferred from Beerse (Belgium) to Diepenbe. They were transported by car to the ek (Belgium) testing facility and subjected to mild exposure (1 hour in a truck, mild) or The samples were subjected to various shipment simulations ranging from severe exposure (4 hours on a plane, high) to severe exposure. The tests were conducted in accordance with 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 It is stored in the tab with the tip facing downwards for more than one month after filling. A packaging order is issued. The syringes are packaged in blister kits and shipped after launch. One day after simulated shipment. Within that time, samples exposed to different simulated shipping conditions in different orientations were shaken at high speed for 5 seconds, and the manufacturing process was carried out. The product is resuspended by manually injecting it into the container, and the injection force is applied to the thumb pad of the syringe. The measurement was taken with the attached sensor. To increase the sensitivity of the test, the product was resuspended. A shorter time (5 seconds instead of 2 x 15 seconds according to IFU) was used for the analysis.

[0137] Store the remaining syringe horizontally or with the tip facing downwards according to the protocol, and re-suspend the syringe. Turbidity / injectability was further evaluated after storage for 1 month, 2 months, or 3 months.

[0138] Furthermore, as described below, the analysis examined the orientation of the syringe before shipment relative to the orientation of shipment. However, this was shown to be an important factor in the resuspension of the product.

[0139] In both single shipments and combinations of truck / air shipments, the initial storage and Maintaining the syringe in the same orientation during shipping makes resuspending the syringe more difficult. Furthermore, after only 5 seconds of high-speed shaking, more residual product was produced.

[0140] The storage location and duration after shipment have only a limited effect on the resuspendability of the product. This represents the factors involved.

[0141] The data provided in Tables 9-11 (below) shows that the syringes have been stored horizontally before shipment and then water-resistant. When shipped flat, compared to syringes stored with the tip facing downwards, it allows for a quick resuspension in 5 seconds. This indicates turbidity and the presence of a larger amount of residual product after injection.

[0142] Similarly, syringes that are stored with the tip facing upward before shipment and then turned with the tip facing downward during shipment are... Rapid resuspension within 5 seconds and, after injection, no residual product present, or very limited residual product. It contained residual products.

[0143] In both single and combined shipments, the syringe is stored during initial storage and shipment. Maintaining the same orientation makes resuspending the syringe more difficult and allows for a rapid 5-second resuspension. More residual product was produced after suspension and manual injection.

[0144] Tables 9-11 provide results for sample sets, showing the same direction during pre-shipment storage and during shipment. Compared to the syringe that was held in place, the orientation during initial storage was different from that during shipment. Allows for direct comparison between syringes.

[0145] Experiments 1 and 2 represent two datasets from trials involving a single type of simulated shipment. On the other hand, Experiment 3 involved a combined shipping test (i.e., simulated air shipment followed by simulated truck shipment). Provides data from the time of shipment.

[0146] [Table 9]

[0147] [Table 10]

[0148] [Table 11]

[0149] These data indicate that syringes shipped in a different orientation than the one they were in during pre-shipment storage were shipped in a different orientation. Syringes maintained in the same orientation during shipping as they were stored beforehand are more easily resuspended than syringes maintained in the same orientation during shipping. It was shown that it had been done.

Claims

1. A method for treating schizophrenia, wherein palmitic acid is administered to a patient suffering from schizophrenia. The procedure involves administering a paliperidone sustained-release injectable suspension from a syringe, the syringe However, the syringe has been stored before shipment and has been shipped, and the syringe that was stored before shipment A method in which the orientation is maintained during shipment in a different orientation from that of the above.

2. The orientation of the product for storage before shipment was with the tip facing downwards, and the orientation of the product for shipment was with the tip facing upwards, The treatment method according to claim 1, wherein the surface is substantially horizontal.

3. The orientation of the pre-shipment storage was with the tip facing downwards, and the orientation of the shipment was substantially horizontal. A treatment method according to claim 1 or claim 2.

4. The suspension contains approximately 273, 410, 546, or 819 mg of paliperide palmitate. A treatment method according to any one of claims 1 to 3, comprising n.

5. The suspension contains approximately 1092 or 1560 mg of paliperidone palmitate. The treatment method according to any one of claims 1 to 4.

6. Improves the resuspension properties of paliperidone palmitate sustained-release injectable suspension in syringes. A method for which, during shipment of the syringe, the orientation of the syringe during storage before shipment is different from A method comprising maintaining the syringe in a different desired orientation.

7. Maintaining the syringe in the desired shipping orientation means that the syringe is placed in the shipping vehicle. To load the syringes in the desired orientation, and to monitor the syringes to ensure that the desired orientation is maintained during shipment. The method according to claim 6, which includes acknowledging or both.

8. The syringe is further housed in a container including an outer surface, the outer surface being front Instructions for maintaining the container during shipment in an orientation corresponding to the desired orientation of the syringe. The method according to claim 6 or claim 7.

9. The syringe is further housed in a container including an outer surface, the outer surface being front A claim having a marking indicating the orientation of the container corresponding to maintaining the desired orientation. The method described in any one of items 6 to 8.

10. After the syringe has been shipped, the syringe is stored in a substantially horizontal position. The method according to any one of claims 6 to 9, further comprising doing the following.

11. Claim 6, the syringe is shipped by airplane, truck, boat, or rail. The method described in any one of the ten items.

12. After the aforementioned shipment, the syringe contains palmitate paliperid that has not been resuspended after administration. The product contains residue of approximately 1.5 mm or less representing n, as described in any one of claims 6 to 11. method.

13. After the aforementioned shipment, the syringe contains palmitate paliperid that has not been resuspended after administration. The method according to any one of claims 6 to 12, which contains residue of approximately 1 mm or less representing n. 。

14. The syringe has a capacity of 1 mL, 2.25 mL, 2.8 mL, or 3 mL, and is long The present invention relates to any one of claims 6 to 13, including a 22 gauge needle that is 1 or 1.5 inches in diameter. method.

15. The syringe has a capacity of 5 mL and includes a 20-gauge needle that is 1.5 inches long. The method according to any one of claims 6 to 13.

16. The suspension contains approximately 273, 410, 546, or 819 mg of paliperide palmitate. The method according to any one of claims 6 to 15, comprising n.

17. The suspension contains approximately 1092 or 1560 mg of paliperidone palmitate. The method according to any one of claims 6 to 15.

18. Any of claims 6 to 17 further comprises administering the suspension to the patient from the syringe. The method described in any one of the items.

19. The desired orientation of shipment is substantially horizontal, tip-up, or tip-down, according to the claim. The method described in any one of items 6 to 18.

20. The desired shipping orientation is approximately 45° to 135° from the orientation of the syringe during storage before shipping. The method according to any one of claims 6 to 19, wherein the degree of change is varied.

21. Whether the orientation for storage before shipment is with the tip facing downwards, and the orientation for shipment is with the tip facing upwards. The method according to any one of claims 6 to 20, wherein the method is, or substantially horizontal.

22. The orientation for pre-shipment storage is with the tip facing downwards, and the orientation for shipment is substantially horizontal. The method according to any one of claims 6 to 21.

23. The force required for injecting a sustained-release paliperidone palmitate injectable suspension from a syringe A method for reducing the amount of the syringe during shipment, while the syringe is being stored before shipment. A method comprising maintaining the syringe in a desired orientation different from the orientation.

24. The force required for injection from the syringe, during pre-shipment storage of the syringe during shipment. Palmitin from the syringe, which was maintained in a direction that was substantially the same as the orientation of the syringe. The force required for injection of paliperidone acid sustained-release injectable suspension is approximately 20% to 50% less. i. The method according to claim 23.

25. The force required for injection from the syringe is directed in the desired direction during shipment of the syringe. Paliperidone palmitate sustained-release injectable suspension from a syringe that was not maintained. The force required for the injection is approximately 10 to 25 Newtons less than the force required for the injection, as described in claim 23 or claim 24. Method of loading.

26. Claim 2, the force required for injection from the syringe is approximately 10 to 25 Newtons. The method described in any one of items 3 to 25.

27. Complete the injection of the paliperidone palmitate sustained-release injectable suspension from the syringe. The method described in any one of claims 23 to 26 further includes evaluating the force required to complete the task. Method of loading.

28. Possibility of incomplete injection of paliperidone palmitate sustained-release injectable suspension from syringe A method for reducing the possibility of the syringe being shipped, and the syringe being stored before shipment A method comprising maintaining the syringe in a desired orientation different from the orientation.

29. The injection of the paliperidone palmitate sustained-release injectable suspension from the syringe is complete. The method according to claim 28, further comprising evaluating whether it has been completed.

30. A collection of syringes, each containing a sustained-release injectable suspension of paliperidone palmitate. The body, and each of the syringes is stored before shipment and shipped to its destination, The syringe, during shipment, is in a different orientation than the syringe in storage before shipment. A collection of syringes, each held in the direction of the rising sun.

31. The assembly according to claim 30, comprising at least 100 individual syringes.

32. Paliperide palmitate in a syringe for administration to patients with schizophrenia. A pharmaceutical product comprising a sustained-release injectable suspension, wherein the syringe has undergone pre-shipment storage. The syringe has been shipped, and the orientation of the syringe is different from the orientation of the syringe during storage before shipment. Pharmaceutical products that are maintained during the aforementioned shipment.

33. The syringe is housed in a container that includes an outer surface, and the outer surface is in front of the syringe. The claim includes instructions for maintaining the container in a orientation corresponding to the desired orientation during shipping. The pharmaceutical product described in 32.

34. The syringe is housed in a container that includes an outer surface, and the outer surface is in front of the syringe. It included markings indicating the orientation of the container corresponding to maintaining the desired orientation. , the pharmaceutical product according to claim 32 or claim 33.

35. After the aforementioned shipment, the syringe contains palmitin that has not been resuspended after injection of the suspension. Any of claims 32 to 34, containing a residue of approximately 1.5 mm or less representing paliperidone acid. A pharmaceutical product as described in item 1.

36. After the aforementioned shipment, the syringe contains palmitin that has not been resuspended after injection of the suspension. Contains a residue of approximately 1 mm or less representing paliperidone acid, any one of claims 32 to 34 Pharmaceutical products as listed in the section.

37. The suspension contains approximately 273, 410, 546, or 819 mg of paliperide palmitate. A pharmaceutical product according to any one of claims 32 to 36, comprising n.

38. The suspension contains approximately 1092 or 1560 mg of paliperidone palmitate. A pharmaceutical product according to any one of claims 32 to 36.

39. The orientation of the syringe during shipping changes by approximately 45° to 135° from the orientation of the syringe during storage before shipping. The pharmaceutical product according to any one of claims 32 to 38.

40. The orientation of the product for storage before shipment was with the tip facing downwards, and the orientation of the product for shipment was with the tip facing upwards, The pharmaceutical product according to any one of claims 32 to 38, wherein the product is substantially horizontal.

41. The orientation of the pre-shipment storage was with the tip facing downwards, and the orientation of the shipment was substantially horizontal. A pharmaceutical product according to any one of claims 32 to 38.

42. The orientation of the syringe during pre-shipment storage was with the tip facing downwards, according to claims 32 to 38. Any of the pharmaceutical products listed in item one.

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