Lipid controlled release composition

Abstract

The present disclosure provides a glass syringe or glass cartridge containing a lipid-based preformulation suitable for refrigerated storage.

Description

Technical Field

[0001] The present disclosure relates to lipid compositions (particularly those suitable for pharmaceutical formulations) and preformulations comprising such lipid compositions. The present disclosure further relates to the use of certain lipid compositions in preventing or reducing the formation of long-lived precipitates during storage of lipid drugs. Background Art

[0002] Many biologically active agents (including drugs, nutrients, vitamins, etc.) have a "functional window." That is, within a concentration range, these agents can be observed to provide a certain biological effect. When the concentration in the appropriate part of the body (e.g., locally or as evidenced by serum concentration) drops below a certain level, the agent cannot produce a beneficial effect. Similarly, there is usually an upper concentration level above which no further benefit can be obtained by increasing the concentration. In some cases, increasing the concentration above a certain level can lead to undesirable or even dangerous effects.

[0003] Some bioactive agents have long biological half-lives and / or wide functional windows, and therefore can be administered occasionally, but can maintain functional bioconcentrations over a considerable period of time (e.g., 6 hours to several days). In other cases, the clearance rate is high and / or the functional window is narrow, so regular (or even continuous) small doses are required to maintain bioconcentrations within the window. When non-oral administration routes (e.g., parenteral administration) are desired or required, this may be particularly difficult (because self-administration may be difficult), and therefore leads to inconvenience and / or poor compliance. In such cases, it would be advantageous to provide therapeutic levels of active agents in a single administration over the entire period of time in which activity is required.

[0004] Some patients receiving treatment often require maintenance of therapeutic doses for considerable periods of time and / or continued treatment for months or years. Therefore, a depot system that allows loading and controlled release of larger doses over a longer period of time would provide a significant advantage over conventional delivery systems.

[0005] Some formulations of the present disclosure produce non-lamellar liquid crystalline phases after use.It is relatively perfect now to use non-lamellar phase structure (such as liquid crystalline phase) in the delivery of bioactivator.A kind of efficient lipid reservoir system is described in WO 2005 / 117830.But, realize that there is still room for the reservoir formulations that improve performance in some aspects.

[0006] In some embodiments, the present invention relates to a lipid-based composition, wherein the composition is a lipid reservoir system, such as the lipid reservoir system described in WO 2005 / 117830, which is stored under refrigeration and then returned to room temperature. The composition may maintain a turbid or "muddy" appearance when the composition is stored under refrigeration. Even after the preformulation is balanced at room temperature, there is still this turbidity. Turbidity is undesirable in injectable drugs and may be prohibited for regulatory and / or safety reasons. As used herein, "turbidity" is used to indicate that the solution lacks clarity. This may be due to the suspension, precipitation, separation or other reasons of the liquid or solid material in the solution.

[0007] Turbidity, including opalescence and the formation of precipitates in the drug (which take a long time to redissolve or remain insoluble), can mean that the drug is more difficult to administer to a subject or in many cases will prohibit such administration. Since some active agents must be stored under refrigerated conditions to prevent degradation of the active agent, the formation of these long-standing precipitates and / or turbidity has the potential to limit the choice of active agents that can be administered as part of such lipid-based formulations in practice.

[0008] Therefore, there is a need to provide a method for preparing lipid-based formulations that have been stored under refrigerated conditions and can be safely administered to a subject without turbidity, opalescence and / or precipitate.

[0009] The present inventors have now determined that lipid-based formulations with reduced turbidity and / or precipitate formation after storage under refrigerated conditions can be provided by preparing the formulation using a high purity diacylglycerol composition (at manufacturing scale) in combination with a specific glass syringe having an inner surface in contact with the lipid-based formulation and containing no silicone oil or even no pre-applied lubricant. By preparing a lipid-based formulation comprising a high purity diacylglycerol composition (such as diolein) and filling in a glass syringe without silicone oil, the formation of precipitate and opalescence / turbidity after storage under refrigerated conditions followed by equilibration at room temperature is unexpectedly reduced while maintaining syringeability. Summary of the invention

[0010] In a first aspect, the present disclosure provides a glass syringe or glass barrel containing a lipid-based preformulation, wherein at least the inner surface of the glass syringe or glass barrel is in contact with the lipid-based preformulation and the inner surface is free of a pre-applied silicone lubricant, and wherein the lipid-based preformulation comprises

[0011] a) 20-80 wt% of diacylglycerols whose fatty acid composition is at least 98% oleic acid (18:1) as determined according to Ph. Eur. 9.0, Method C, 2.4.22 (Fatty acid composition by gas chromatography);

[0012] b) 20-80 wt% of phospholipids;

[0013] c) 1-30 wt % of a solvent;

[0014] d) biologically active agents;

[0015] wherein a) and b) account for at least 94 wt% of the total lipid content of the lipid-based preformulation, and the lipid-based preformulation is a clear liquid having a viscosity of less than 1000 mPas at 20°C and is substantially free of visible precipitate after storage at a temperature of less than or equal to 10°C, such as 0°C-10°C, such as 2°C-8°C for at least 1 month followed by equilibration at room temperature for a period of at least one hour, according to USP <790> Determined.

[0016] In one aspect, the glass syringe or glass barrel contains a lipid-based preformulation, wherein the preformulation contains or consists of: no more than (NMT) 6000 particles greater than or equal to 10 μm (sediment and / or turbidity) and / or NMT 600 particles greater than or equal to 25 μm (sediment and / or turbidity), as defined by USP <788> Determined.

[0017] Viewed from a second aspect, the present disclosure provides a method of administering a lipid-based preformulation compressed in a glass syringe or glass barrel according to the attached claims and the embodiments and aspects described herein to a patient in need thereof, wherein the glass syringe or glass barrel containing the preformulation is maintained at a temperature of less than or equal to 10°C, such as 0°C-10°C, such as 2°C-8°C prior to administration, and is allowed to equilibrate at room temperature prior to administration.

[0018] Viewed from a third aspect, the present disclosure provides use of a diacylglycerol composition having a fatty acid composition of at least 98% oleic acid (18:1) as determined according to Ph. Eur. 9.0, Method C, 2.4.22 (Fatty acid composition by gas chromatography), in preventing or reducing the formation of long-lived precipitates in a preformulation comprising the diacylglycerol composition and at least one biocompatible organic solvent.

[0019] Viewed from a fourth aspect, the disclosure provides a method for preventing or reducing the formation of long-lived precipitates in a preformulation when the preformulation is stored at a temperature of 0°C to 10°C, such as 2°C to 8°C for a period of at least 24 hours, such as at least 1 month, such as at least 3 months, such as at least 6 months, the preformulation comprising:

[0020] (i) a diacylglycerol composition; and

[0021] (ii) at least one biocompatible organic solvent;

[0022] The method comprises forming the preformulation with the diacylglycerol composition according to the first aspect. An example of the fourth aspect is a method for preventing or reducing the formation of long-lived precipitates in a lipid-based preformulation when the preformulation is stored at a temperature of 0°C to 10°C, such as 2°C to 8°C, for a period of at least 24 hours, such as at least 1 month, such as at least 3 months, such as at least 6 months, the lipid-based preformulation comprising:

[0023] a) (i) 20-80 wt% of diacylglycerols whose fatty acid composition is at least 98% oleic acid (18:1) as determined according to Ph. Eur. 9.0, Method C, 2.4.22 (Fatty acid composition by gas chromatography);

[0024] b) 20-80 wt% of phospholipids;

[0025] c) 1-30 wt % of a solvent;

[0026] d) Bioactive agents.

[0027] From the fifth aspect, the present disclosure provides a pre-filled glass syringe or glass barrel according to the first aspect, which is pre-filled with a lipid-based composition and comprises a syringe having an inner surface, wherein the inner surface portion of the syringe that is always in contact with the lipid-based composition is substantially free of any pre-applied lubricant (i.e., free of silicone oil and any other pre-applied lubricant), wherein being substantially free of any pre-applied lubricant should be understood as not adding lubricants during or after the manufacture of the syringe, i.e., the inner surface is substantially free of lubricants, such as silicone oil, before the syringe is filled with the lipid-based composition disclosed herein. Examples of suitable syringes are commercially available, such as those sold by Gerresheimer, Schott, and BD (Becton, Dickinson and Company), for example, 1 mL glass syringes, provided that the inner surface is free of silicone oil or free of lubricants.

[0028] In another aspect, the present disclosure provides a method of administering a preformulation according to the present disclosure contained in a syringe free of silicone oil to a patient in need thereof, wherein the syringe containing the preformulation is maintained at refrigerated temperature (e.g., between 2°C and 8°C) until about 1 hour before administration (e.g., up to 24 months before administration), and is allowed to equilibrate at room temperature (15°C-25°C, e.g., at 25°C) for about 1 hour before administration.

[0029] The preformulation should be a clear liquid, i.e., without visible turbidity (turbidity) upon administration. Turbidity can be determined according to USP <790> Check by visual inspection.

[0030] In another aspect, the present disclosure provides a syringe according to the first aspect, wherein the stability of the preformulation is at least six months, such as at least 12 months, such as at least 18 months, stored at 2°C-8°C.

[0031] In another aspect, the disclosure provides a syringe according to the first aspect, wherein the syringe is provided with a stopper. Examples are commercially available stoppers from BD or West suitable for syringes described herein, such as 1 mL glass syringes.

[0032] Further aspects and embodiments are provided in the dependent claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 : Photographs taken under polarized light of a prefilled syringe according to the present disclosure stored at 5°C for 14 months, taken at 0 minutes, 5 minutes, 15 minutes and 30 minutes after removal from the climate chamber.

[0034] Figure 2a and Figure 2b Shown are plots of injection time versus glide force for formulations of varying viscosities injected through 22G TW and 23G UTW needles, respectively.

[0035] Figure 3 The correlation between the estimated sliding and break-loose forces is shown.

[0036] Figure 4 and Figure 5 : Photograph of a prefilled glass syringe according to Example 2. DETAILED DESCRIPTION

[0037] The present disclosure provides a high purity diacylglycerol composition. As used herein, the term "high purity diacylglycerol composition" is understood to mean a composition or formulation comprising at least 97.0 wt% of diacylglycerols having two fatty acid residues, each having 16-20 carbon atoms and one or two carbon-carbon double bonds, for example, a fatty acid composition of at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of fatty acid composition by gas chromatography) of European Pharmacopoeia 9.0.

[0038] Unless otherwise noted, all % are specified by weight in the full text of this article.Weight percentage (%) can be abbreviated as, for example, wt%.In addition, unless otherwise noted, the weight % indicated is the total composition or formulation % including all components indicated herein.Unless otherwise noted, when the weight percentage associated with the salt of the active agent compound is given, the weight percentage is related to the amount (or equivalent) of the free alkali.In some instances, the wt% of a specified salt is provided (but indicated in appropriate cases), and the corresponding weight of the free alkali can be easily converted into.

[0039] When a composition or formulation is expressed herein as "consisting essentially of certain components," the specified component provides the essential properties of the formulation, such as when the specified component constitutes at least 95%, preferably at least 98%, of the formulation. The same applies to any component or ingredient that may be formed from more than one material. Similarly, when any use of "about," "about," "approximately," or similar language appears herein, this indicates that the specified amount is a primary embodiment, but the actual amount should not vary significantly from the specified amount, as judged by a person skilled in the art. Unless the context prohibits, this will generally be ±10%, ±5%, or ±1% of the specified value.

[0040] Herein, particularly with reference to the claims, where the language "comprising" an agent or "consisting of an agent" or a component "selected from the group consisting of," the language is used to indicate two embodiments; an open group of "comprising" embodiments and a closed group of "consisting of embodiments." In the latter case, the list of agents and components is considered closed and can be considered to end with the last instance of the "and" list. Thus, the language can be read as "selected from the group consisting of and."

[0041] Whenever the terms "comprising" or "containing" are used in aspects, embodiments, claims, etc. of the present disclosure, such terms should be understood to encompass aspects, embodiments, and claims in which the terms have been replaced with "consisting essentially of" or "consisting of." A specific example is that whenever the term "a glass syringe or glass barrel containing a lipid-based preformulation" appears, the following are also considered to be explicitly contemplated: "a glass syringe or glass barrel consisting essentially of a lipid-based preformulation" and "a glass syringe or glass barrel consisting of a lipid-based preformulation."

[0042] Unless the context prohibits, when any active agent (e.g., a drug or API) is indicated herein, this also discloses the active agent in the form of any pharmaceutically acceptable salt. Suitable pharmaceutical salts are well known in the art, and suitable examples of all embodiments are described herein. Salts such as halides (especially chlorides), acetates, pamoates, etc. are examples of suitable salts of the base moiety. Alkali metal, alkaline earth metal, amine or alkylamine salts are examples of suitable salts of the acid moiety.

[0043] The term "precursor formulation" or preformulation is used herein to refer to a pharmaceutical formulation that can be injected to produce a controlled release "depot" formulation in a subject. The preformulation may optionally consist essentially only of the components indicated herein (including other optional components indicated herein below and in the appended claims, where appropriate), and in one aspect consists entirely of such components.

[0044] In one embodiment, the diacylglycerol composition of any suitable aspect comprises at least 97.5 wt%, such as at least 98.0 wt%, such as at least 98.5 wt%, of diacylglycerols having two fatty acid residues, each independently having 16-20 carbon atoms and one or two carbon-carbon double bonds. In one embodiment, the diacylglycerol composition consists essentially of diacylglycerols having two fatty acid residues, each independently having 16-20 carbon atoms and one or two carbon-carbon double bonds, for example, diolein with a fatty acid composition of at least 98% oleic acid (18:1) as determined according to Ph. Eur. 9.0, Method C, 2.4.22 (Fatty acid composition by gas chromatography).

[0045] Although diacylglycerol compositions are known in the prior art, diacylglycerol compositions having as high a purity as the diacylglycerol compositions of the present disclosure have not previously been used to manufacture pharmaceutical products (e.g., lipid-based preformulations such as those described herein) and for use in combination with glass syringes or glass barrels that do not contain a pre-applied silicone lubricant (e.g., silicone oil).

[0046] Surprisingly, the present inventors have determined that when a lipid-based formulation is produced using the highly pure diacylglycerol compositions of the present disclosure rather than the (less pure) conventional diacylglycerol compositions known in the prior art, the turbidity observed upon thawing of the lipid-based composition after having been stored under refrigerated conditions is reduced or eliminated (e.g., according to USP <790> The present inventors have also identified a method by which diacylglycerols can be synthesized with high purity.

[0047] Without wishing to be bound by theory, it is believed that the presence of saturated impurities in the lipid-based composition results in the turbidity observed when a formulation incorporating the composition is stored under refrigerated conditions and then equilibrated at room temperature. By preparing the formulation with a highly pure diacylglycerol composition, the amount of saturated impurities in the formulation can be reduced, thereby also reducing the amount of insoluble long-lived precipitates formed after refrigerated storage followed by thawing.

[0048] Thus, in one embodiment, the diacylglycerol composition comprises less than 3 wt% saturated fatty acid residues. In one embodiment, the diacylglycerol composition comprises less than 2 wt%, such as less than 1 wt%, saturated fatty acid residues. The amount of saturated fatty acid residues in the diacylglycerol composition can be measured by any means known in the art, such as gas chromatography (GC). A particularly suitable method can be found in Method C, 2.4.22 (Determination of fatty acid composition by gas chromatography) of European Pharmacopoeia 9.0.

[0049] The desired diacylglycerol fatty acid residues each independently have 16-20 carbon atoms. In one embodiment, the diacylglycerol fatty acid residues each independently have 16-20 carbon atoms. In one embodiment, the fatty acid residues each independently have 16 or 18 carbon atoms. In one embodiment, the fatty acid residues each have 16 carbon atoms or each have 18 carbon atoms. In one embodiment, the fatty acid residues each have 18 carbon atoms.

[0050] The fatty acid residues of the desired diacylglycerols each independently have one or two carbon-carbon double bonds. In one embodiment, the fatty acid residues of the diacylglycerols each have 1 carbon-carbon double bond or each have 2 carbon-carbon double bonds. In one embodiment, the fatty acid residues each have 1 carbon-carbon double bond.

[0051] In one embodiment, the fatty acid residues of the diacylglycerols are independently oleic acid residues (C18: 1) or linoleic acid residues (C18: 2). The name "CX: Z" means a hydrocarbon chain with X carbon atoms and Z unsaturations (especially double bonds). In one embodiment, the fatty acid residues are each oleate residues or each linoleate residue. In one embodiment, the fatty acid residues are each oleate residues, that is, the diacylglycerols are diolein. In all aspects of this paper, a key embodiment is that the diacylglycerols referred to herein can be diolein, dilinolein or a mixture thereof. In one embodiment, the diacylglycerols referred to herein in all aspects can be diolein.

[0052] In one embodiment, the diacylglycerol having two fatty acid residues, each having 16-20 carbon atoms and one or two carbon-carbon double bonds, is a mixture of 1,2-diacylglycerol and 1,3-diacylglycerol isomers. In one embodiment, the isomer ratio of 1,2-diacylglycerol to 1,3-diacylglycerol is between 5:1 and 1:5, such as between 4:1 and 1:4, such as between 1:1.5 and 1:3.5 (e.g., 1:2 to 1:3).

[0053] In one embodiment, the diacylglycerol composition comprises no more than 2 wt%, such as no more than 1.5 wt%, such as no more than 1 wt%, such as no more than 0.5 wt% of monoacylglycerol. In one embodiment, the diacylglycerol composition comprises no more than 2.5 wt%, such as no more than 2 wt%, such as no more than 1.5 wt% of triacylglycerol.

[0054] Preformulations

[0055] In one aspect, the present disclosure relates to a precursor formulation (also referred to as a "preformulation") comprising: i) a diacylglycerol composition whose fatty acid composition is at least 98% oleic acid (18:1) as determined according to Ph. Eur. 9.0, Method C, 2.4.22 (Fatty acid composition by gas chromatography); and ii) at least one biocompatible organic solvent. The diacylglycerol composition component i) may be a diacylglycerol composition described herein.

[0056] As used herein, the term "formulation" or "preformulation" relates to a mixture of components (i) and (ii) and optionally other components. The preformulation generally has a low viscosity. The term "preformulation" means that the preformulation forms or is capable of forming at least one non-lamellar (especially liquid crystalline) phase structure after contact with an excess of an aqueous fluid.

[0057] The term "depot" relates to a composition formed after a preformulation is exposed to an excess of aqueous fluid (e.g., during parenteral administration). Without wishing to be bound by theory, it is believed that this change is caused at least in part by exchanging solvent (ii) for an aqueous fluid and / or by adding an aqueous fluid to the lipid structure. The depot typically has a much higher viscosity than the corresponding preformulation and provides for a gradual release of any active agent contained in the depot.

[0058] In one embodiment, the preformulation of the present disclosure produces a non-lamellar phase (e.g., a non-lamellar liquid crystalline phase) after administration. It is relatively perfect to use a non-lamellar phase structure (such as a liquid crystalline phase) in the delivery of a bioactive agent. Effective lipid reservoir systems are described in WO 2005 / 117830 (incorporated herein by reference). For the description of the most favorable phase structure of this type of preparation, please note the discussion in WO 2005 / 117830, particularly its 29th page. Preferably, the preformulation according to the present disclosure has a molecular solution or L2 phase structure before administration.

[0059] The preformulation of the present disclosure forms or is capable of forming at least one liquid crystalline phase structure after contacting with excess aqueous fluid. In this article, "excess aqueous fluid" is understood to be an aqueous fluid having a volume that is at least 10 times (such as 10 to 1000 times) greater than the volume of the preformulation.

[0060] In one embodiment, applicable to all aspects of the present disclosure, the preformulation according to the present disclosure has a molecular solution or L2 phase structure (before application). The preformulation forms a non-lamellar (e.g., liquid crystal) phase after application. This phase transition is usually caused by absorbing aqueous fluids from a physiological environment, as indicated herein. Although previously determined in WO 2012 / 160213, as long as there is a monohydric alcohol solvent, water of a strictly controlled amount can be tolerated, it should be understood that after application, the preformulation is exposed to a large amount of aqueous fluids in vivo, which leads to the formation of a non-lamellar phase. Typically, the preformulation will form a non-lamellar phase after contacting with at least an equal volume of aqueous fluid.

[0061] The viscosity of the preformulations of the present disclosure will be controlled by their formulation, but will generally be within a range that can be effectively delivered by a syringe or autoinjector within a tolerable period of time (e.g., less than 30 seconds). Suitable viscosities may be 10 to 1000 mPas at 25° C., such as 100 to 800 or 200 to 600 mPas at 25° C. A viscosity of 300 to 500 mPas at 25° C. may be suitable.

[0062] Component (i): diacylglycerol composition

[0063] The preformulation of the present disclosure comprises a diacylglycerol composition whose fatty acid composition is at least 98% oleic acid (18:1) as determined according to Method C, 2.4.22 (determination of fatty acid composition by gas chromatography) of Pharmacopoeia Europe 9.0. In one embodiment, the diacylglycerol composition is the only diacylglycerol present in the preformulation, i.e., the preformulation does not substantially contain any diacylglycerols other than the diacylglycerol composition whose fatty acid composition is at least 98% oleic acid (18:1) as determined according to Method C, 2.4.22 (determination of fatty acid composition by gas chromatography) of Pharmacopoeia Europe 9.0.

[0064] The main difference between the preformulations of the present disclosure and those known in the prior art is that the preformulations of the present disclosure comprise a high purity diacylglycerol composition as defined herein. Surprisingly, the inventors have determined that when the high purity diacylglycerol composition of the present disclosure (optionally in combination with a syringe having an inner surface without a pre-applied lubricant) is used to prepare the preformulation, the formation of long-lived precipitates in the composition after storage under refrigerated conditions (e.g., 2° C. to 8° C.) is reduced and can be prevented (e.g., after storage for a month or more).

[0065] Without being bound by theory, it is believed that the formation of long-lived precipitates in prior art formulations after storage under refrigerated conditions is due to the presence of saturated impurities in the lipid component. The use of the highly purified diacylglycerol compositions of the present disclosure reduces the level of saturated impurities in the formulation and thus prevents or reduces the formation of such long-lived precipitates.

[0066] Component (ii): Biocompatible organic solvent

[0067] The component (ii) of the preformulation of the present disclosure is at least one biocompatible organic solvent. Component (ii) can be a single solvent or a mixture of two or more solvents. Because the preformulation produces or can produce a reservoir composition after contacting with an excessive amount of aqueous fluid after administration (for example, in vivo), it is desirable that these solvents are tolerated to the subject and can be mixed with aqueous fluids and / or diffused or dissolved in aqueous fluids from the preformulation. Therefore preferably there is at least a medium water-soluble solvent. As will be described below, component ii) can include a polar cosolvent, such as propylene glycol.

[0068] As used herein, the term "biocompatible organic solvent" is understood to be a solvent that can be safely used in mammalian subjects (e.g., humans). Typically, a biocompatible organic solvent will have an LD50 (as calculated by oral administration in rats) greater than 700 mg / kg (such as greater than 1000 mg / kg, especially greater than 1500 mg / kg). LD50 data for common solvents can be easily obtained in MSDS tables.

[0069] In an embodiment, component ii) comprises or consists of at least one solvent selected from the group consisting of alcohols, amines, amides and esters. Preferably, component ii) comprises at least one monohydric alcohol solvent. Most preferably, component ii) comprises ethanol, propanol, isopropanol or a mixture thereof. Particularly preferably, component ii) comprises or consists of ethanol. Component ii) may comprise or consist of a monohydric alcohol solvent (preferably ethanol) and a polar co-solvent. A mixture comprising or consisting of ethanol and propylene glycol is suitable. In an embodiment, the biocompatible organic solvent is a biocompatible oxygenated organic solvent.

[0070] Examples of solvents are ethanol, propylene glycol (PG), water for injection (WFI), benzyl alcohol, dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP) and mixtures thereof. In some embodiments disclosed herein, the solvent is ethanol, propylene glycol (PG), dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP) and mixtures thereof.

[0071] Component (ii) may comprise two or more components from the above solvent list, in particular a monohydric alcohol solvent and a solvent selected from amides, sulfoxides or dihydric alcohol solvents. Any one or more solvents that are not monohydric alcohol solvents may be referred to herein as co-solvents. When there are two or more solvents, suitable combinations include ethanol and amides (such as ethanol and N-methylpyrrolidone (NMP)), ethanol and sulfoxides (such as ethanol and dimethyl sulfoxide (DMSO)) or ethanol and dihydric alcohol solvents or polyol solvents (such as ethanol and propylene glycol (PG)). Ethanol and PG form an embodiment.

[0072] A suitable combination of solvents is ethanol and PG, particularly when the ratio of ethanol to PG is 1:5 to 20:1, such as 1:1 to 10:1, such as 1.5:1 to 8:1, such as 2:1 to 5:1 (e.g., about 3:1, such as 2.8:1 to 3.2:1). In one embodiment, component (ii) may be a biocompatible oxygenated solvent, such as a solvent selected from the group consisting of ethanol, NMP, propylene glycol, benzyl alcohol, DMSO, dimethylformamide, dimethylacetamide, and mixtures thereof. Component (ii) may comprise or consist of ethanol, or may comprise or consist essentially of a mixture of ethanol and PG. In one embodiment, component (ii) comprises or consists essentially of propylene glycol.

[0073] The amount of component (ii) in the preformulation will have a considerable impact on several characteristics. In particular, viscosity and release rate (and duration) will vary significantly with solvent level. Therefore, the amount of solvent will be at least enough to provide a low viscosity mixture, but the amount of solvent will be determined in addition to provide the required release rate. This can be determined by conventional methods according to the following examples. Usually, the level of 1% to 30% (particularly 2% to 25%) solvent will provide suitable release and viscosity characteristics. This will preferably be 2% to 20%, preferably 5% to 15%, and an amount of about 10% (e.g., 10% ± 3%) is efficient. These levels include any co-solvents present as a part of component (ii), as mentioned above.

[0074] As noted above, the amount of component (ii) in the preformulations of the present disclosure will be at least sufficient to provide a low viscosity mixture (e.g., a molecular solution) of components (i) and (ii), and will be readily determined by standard methods for any particular combination of components.

[0075] The phase behavior of any preformulation, composition or mixture can be analyzed by techniques such as visual observation combined with polarized light microscopy, X-ray scattering and diffraction techniques, nuclear magnetic resonance and cryogenic transmission electron microscopy (cryo-TEM) to observe the solution, L2 or L3 phase, or liquid crystalline phase or dispersed fragments of such phases in the case of cryoTEM. Viscosity can be measured directly by standard means. As described herein, a suitable actual viscosity is a viscosity that can be effectively injected and particularly sterile filtered. This will be easily assessed as indicated herein.

[0076] It is preferred that component ii) contains little or no halogen-substituted hydrocarbons, as these tend to have lower biocompatibility.

[0077] As used herein, component (ii) can be a mixture of a single solvent or a suitable solvent, but generally has low viscosity. This is very important because one of the key aspects of the disclosure is that it provides a low-viscosity preformulation, and the main effect of a suitable solvent is to reduce the viscosity. This reduction will be due to the combination of the influence of a lower solvent viscosity and the influence of the molecular interaction between the solvent and the lipid composition. An observation of the inventor is that the low-viscosity oxygenated solvent described herein has a very favorable and unexpected molecular interaction with the lipid portion of the composition, thereby providing a nonlinear reduction in viscosity when adding a small volume of solvent.

[0078] The viscosity of the "low viscosity" solvent component (ii) (single solvent or mixture) should generally not exceed 18 mPas at 20° C. It is preferably not more than 15 mPas, more preferably not more than 10 mPas, and most preferably not more than 7 mPas at 20° C.

[0079] In WO 2012 / 160213, it is described that adding polar solvents in addition to monoalcohol solvents leads to many advantages, including reduced viscosity and reduced active agent burst profile. In addition to the preferred aspects previously described for component ii), in a particularly preferred embodiment, component ii) comprises a monoalcohol solvent and a polar co-solvent. As used herein, the term "polar co-solvent" defines a solvent having a dielectric constant (diel) of at least 28 at 25°C, more preferably at least 30 at 25°C, but not water or any aqueous fluid. Very suitable examples include propylene glycol (diel about 32) and N-methyl-2-pyrrolidone (NMP, diel about 32). Unless the context otherwise permits, the preferred levels of component ii) described herein also apply to mixtures of monoalcohol solvents and polar co-solvents.

[0080] Typical cosolvents will have a relatively high dielectric constant corresponding to their high polarity. Thus, suitable cosolvents generally have a dielectric constant of at least 28 at 25°C, more preferably at least 30 at 25°C. Very suitable examples include water (about 80), propylene glycol (about 32), dimethyl sulfoxide (about 47) and N-methyl-2-pyrrolidone (NMP, about 32). Propylene glycol is particularly useful in combination with some active agents.

[0081] In a particularly preferred embodiment, component ii) comprises, consists essentially of, or consists of a mixture of a monohydric alcohol solvent and a polar cosolvent. In one embodiment, the polar cosolvent may be a dihydric alcohol C3-C6 organic solvent, i.e., a C3-C6 organic solvent comprising two hydroxyl groups. The dihydric alcohol solvent is preferably propylene glycol. When present, the polar cosolvent is included at a level of 2 to 12 wt.% (such as 3 to 10 wt.%, especially 4 to 9 wt.%) of the preformulation. This level is counted as part of the range of component ii) above. Most preferably, component ii) comprises, consists essentially of, or consists of a mixture of ethanol and propylene glycol (PG).

[0082] When both an organic monoalcohol solvent and a polar cosolvent are present, such as ethanol and PG, the ratio of the monoalcohol solvent to the polar cosolvent is preferably in the range of 20:80 to 70:30, preferably 30:70 to 70:30 (w / w), more preferably 40:60 to 60:40. Approximately equal amounts of the monoalcohol and diol components are very suitable.

[0083] In particularly preferred embodiments, component ii) is present at a level of 1% to 30% and comprises, consists of or consists essentially of a mixture of ethanol and PG, wherein the ratio (w / w) of ethanol to PG is in the range of 30:70 to 70:30, preferably 40:60 to 60:40. More preferably, component ii) is present in the range of 5 to 15 wt% or 8 to 18 wt%, most preferably 8-18 wt%, and is a mixture of ethanol and PG in a ratio of 40:60 to 60:40 (w / w).

[0084] For the avoidance of doubt, even when a polar co-solvent is present in the pre-formulations of the present disclosure, the total water content will remain as described in the various Examples herein (eg, 0.1 to 1.0 wt %).

[0085] In some embodiments, particularly suitable combinations of solvents for component (ii) include monohydric alcohol solvents and cosolvents selected from the group consisting of amides, sulfoxides, or glycols. Particularly preferred combinations are ethanol and amides, ethanol and sulfoxides, or ethanol and glycols. Particularly preferred combinations are ethanol and propylene glycol (PG); ethanol and dimethyl sulfoxide (DMSO); and ethanol and N-methyl-pyrrolidone (NMP).

[0086] When present, the suitable amount of cosolvent will generally be greater than 1% by weight of the preformulation, such as 2%-15%, particularly 4%-12%, especially 4-10wt.%. The combination of monoalcohol solvent and cosolvent as component (ii) has potential advantages in the composition of the present disclosure. In particular, by including some cosolvents that are miscible with the monoalcohol component, the slight sensation that may be caused by the alcohol content at the injection site can be substantially eliminated. Therefore, in one embodiment, the ratio of monoalcohol component: cosolvent can be in the range of 30:70 to 90:10, more preferably 50:50 to 80:20, especially 60:40 to 80:20. Approximately equal amounts of components (w / w) are very suitable.

[0087] Optional phospholipid component

[0088] In one embodiment, the preformulation of the present disclosure comprises a phospholipid component.

[0089] In embodiments, the phospholipid component is present in an amount of 15 to 50 wt.% of the preformulation. In some embodiments, the amount of phospholipid may be 15 to 45 wt.%, such as 20 to 45 wt.%.

[0090] In an embodiment, the ratio of diacylglycerol composition:phospholipid is 35:65 to 65:35 (w / w), such as 40:60 to 60:40, such as 45:55 to 55:45. A ratio of around 50:50 (e.g., ±2) is particularly suitable.

[0091] Phospholipids include a polar head group and at least one non-polar tail group. In one embodiment, a phospholipid (e.g., phosphatidylcholine (PC)) will include two non-polar groups. In particular, C12 to C20 (such as C16 to C18) acyl groups with zero, one or two unsaturations (e.g., 1 or 2 unsaturations) in either case are well suited as part of the non-polar groups forming the phospholipids. In an embodiment, at least 50% of the non-polar groups are oleoyl groups (C18:1).

[0092] In one embodiment, at least 50% (such as at least 75% or at least 90%) of the non-polar groups of the phospholipids are C16 to C18 (e.g., C18: 1) moieties. In one embodiment, about 100% of the non-polar groups of the phospholipids are such moieties.

[0093] In another embodiment, at least 50% (such as at least 75% or at least 90%) of the non-polar groups of the phospholipids are C18 (e.g., C18: 1) moieties. In one embodiment, about 100% of the non-polar groups of the phospholipids are such moieties.

[0094] In embodiments, the phospholipids comprise or consist of a phospholipid that does not form a non-lamellar liquid crystalline phase structure as a pure compound in water at 25° C. In embodiments, the phospholipids comprise or consist of a phospholipid that forms a non-lamellar liquid crystalline phase structure (e.g., a hexagonal liquid crystalline phase structure) in water at 25° C.

[0095] The phospholipid portion may be derived from natural sources. Suitable sources of phospholipids include eggs, heart (e.g., cattle), brain, liver (e.g., cattle), and plant sources, including soybeans. Such sources may provide one or more components of the phospholipid component, which may include any mixture of phospholipids.

[0096] Suitable polar head groups of phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol. In one embodiment, the preformulation comprises a phospholipid selected from the group consisting of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI) and mixtures thereof. It has been shown in WO 2013 / 038460 and WO 2013 / 083459 that the use of at least 50% PE (by weight) of the total amount of phospholipids can lead to improved depot robustness.

[0097] In an embodiment, the phospholipids comprise or consist of one or more PCs. For example, at least 50% of the head groups of the phospholipids should be PCs, such as more than 65% head groups, especially more than 85% or more than 90%. PCs from a single source (e.g., soy PCs) or mixtures of PCs from different sources (e.g., soy PCs and egg PCs) can be used. In an embodiment, the PC component contains at least 50% soy PCs, such as at least 75% soy PCs or substantially pure soy PCs. In an embodiment, the PC component contains at least 50% egg PCs, such as at least 75% egg PCs or substantially pure egg PCs.

[0098] In one embodiment applicable to all aspects of the present disclosure, the phospholipid comprises or consists of PC, such as PC derived from soybeans (soy PC). PC is available from various suppliers including Lipoid. Naturally derived PC typically comprises 18:2 fatty acids as the major fatty acid component and 16:0 and / or 18:1 as minor fatty acid components. In embodiments, the ratio between (18:2 fatty acids: other fatty acids) is 1.5:1 and 6:1. PC having approximately 60%-65% 18:2, 10% to 20% 16:0 and 5%-15% 18:1 and the remainder being primarily other 16-carbon and 18-carbon fatty acids is particularly suitable and is a typical soybean PC.

[0099] In an alternative but equally suitable embodiment, which is also applicable to all aspects of the present disclosure, the PC component may comprise synthetic dioleoyl PC (DOPC). This is believed to provide increased stability and would therefore be particularly useful in compositions that need to be stable under long-term storage and / or have a long release period in vivo. In this embodiment, the PC component contains at least 50% synthetic dioleoyl PC, such as at least 75% synthetic dioleoyl PC, and may be substantially pure synthetic dioleoyl PC.

[0100] In one embodiment, the preformulation of the present disclosure consists at least in part of synthetic DOPC (i.e., PC having at least 95% PC head groups and at least 90% oleyl (C18:1) acyl groups) and has storage stability at 15°C-25°C, defined as less than 5% degradation of the active agent after at least 6 months, such as at least 12 months or at least 24 months (as determined by HPLC).

[0101] Since the preformulations of the present disclosure will be administered to a subject, it is important that the components are biocompatible. In this regard, both PC and DAG are well tolerated and break down in vivo into components naturally present in mammals.

[0102] Synthetic or highly purified PCs such as dioleoylphosphatidylcholine (DOPC) and palmitoyloleoylphosphatidylcholine (POPC), as well as various other high purity PCs described herein, are very suitable as all or part of the phospholipids. As used herein, the term "highly purified" refers to PC derived from natural sources that have been refined to remove contaminants. As used herein, the term "synthetic or highly purified" PC refers to a material comprising at least 95 wt% phosphatidylcholine, wherein the two acyl chains within the PC each independently have 16 to 20 carbons, at least one acyl chain has at least one unsaturation in the carbon chain and no more than four unsaturations on both carbon chains.

[0103] Typically this will be a phospholipid wherein at least 95% of the phospholipids have a PC head group and at least 95% are C16 to C20 acyl chains having from 0 to 3 degrees of unsaturation.

[0104] In an embodiment, the synthetic PC is DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine). In other embodiments, the synthetic PC may comprise or consist of DDPC (1,2-didecanoyl-sn-glycero-3-phosphocholine); DEPC (1,2-dierucoyl-sn-glycero-3-phosphocholine); DLOPC (1,2-dilinoleoyl-sn-glycero-3-phosphocholine); DLPC (1,2-dilauroyl-sn-glycero-3-phosphocholine); DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine); DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine); DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine); DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine); MPPC (1-myristoyl-sn-glycero-3-phosphocholine); The invention relates to a poly(1-palmitoyl-2-palmitoyl-sn-glycero-3-phosphocholine) comprising: a poly(1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine) comprising: a poly(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) comprising: a poly(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) comprising: a poly(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) comprising: a poly(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) comprising: a poly(1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine) comprising: a poly(1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine) comprising: a poly(1-stearoyl-2-palmit ... In all cases, the synthetic PC will preferably contain no more than 5% (eg, 0.01% to 5%) of other materials, such as no more than 2% or no more than 1% of other materials.

[0105] Active Agent

[0106] The preformulation of the present disclosure comprises an active agent, also referred to as a bioactive agent. The preformulation of the present disclosure optionally comprises one or more peptides or non-peptide active agents. It is important to note that the present disclosure is generally applicable, and therefore it is envisioned that the present disclosure is applicable to preformulations containing any bioactive agent of interest (particularly an active agent that requires refrigerated storage) or even completely free of a bioactive agent. The bioactive agent can be any compound with a desired biological or physiological effect, such as a peptide, protein, drug, antigen, nutrient, cosmetic, spice, seasoning, diagnostic agent, medicine, vitamin or dietary agent, and will be formulated at a level sufficient to provide a functional level of in vivo concentration (including the local concentration of a topical composition). Suitable active agents include medicaments (including drugs, vaccines and diagnostic agents). A class of active agents applicable to certain embodiments is somatostatin and somatostatin analogs, examples of which are selected from the group consisting of SST-14, SST-28, octreotide, lanreotide, pasireotide and vapreotide or their salts. In some aspects of the present disclosure, the bioactive agent is octreotide. In some aspects of the present disclosure, the bioactive agent is SST-14.

[0107] In one embodiment, the active agent is an active agent that requires refrigeration, i.e., an active agent that will degrade if stored at room temperature for an extended period of time. As used herein, an active agent in a relevant formulation will degrade such that if the active agent (if appropriate, in a formulation) is stored at 25°C for a period of 18 months, less than 90% of the active agent will remain (e.g., as measured by HPLC), then the active agent "requires refrigeration". Examples include active agents that degrade to 90% or less of their original level when stored at 25°C for less than 18 months, such as 12 months (e.g., 1 to 12 months), 6 months, or 3 months.

[0108] In one embodiment, the active agent is one that degrades to less than 90 wt % of the original level when stored at room temperature (eg, 25° C.) for a period of 12 months.

[0109] Examples of active agents that can be delivered by the compositions of the present disclosure include, but are not limited to, antibacterial agents, immunomodulators (including immunostimulants and immunosuppressants), anticancer and / or antiviral drugs (such as nucleoside analogs, paclitaxel and their derivatives), anti-inflammatory drugs / anti-inflammatory agents (such as non-steroidal anti-inflammatory drugs and corticosteroids), cardiovascular drugs (including cholesterol-lowering and blood pressure-lowering agents), analgesics, antiemetics (including histamine H1, NK1 and 5-HT3 receptor antagonists), corticosteroids and cannabinoids, antipsychotics and antidepressants (including serotonin uptake inhibitors), prostaglandins and derivatives, vaccines and bone regulators. Diagnostic agents include radionuclide labeled compounds and contrast agents, including X-ray, ultrasound and MRI contrast enhancers. Nutrients include vitamins, coenzymes, dietary supplements, etc.

[0110] Particularly suitable active agents include those that usually have a short residence time in the body due to rapid decomposition or excretion and those with poor oral bioavailability, alternatively wherein long duration of action will be beneficial. These include active agents based on peptides, proteins and nucleic acids, hormones and other naturally occurring agents in their natural or modified forms. By administering such agents in the form of a depot composition (which is formed by the composition disclosed herein), these agents provide a time length that can be extended to several days, weeks or even months at a sustained level, despite having a rapid clearance rate. This provides a significant advantage over multiple daily dosings in the same period in terms of stability and patient compliance. In one embodiment, the active agent therefore has a biological half-life (after entering the bloodstream) of less than 1 day, such as less than 12 hours, for example, less than 6 hours. In some cases, this may be as low as 1-3 hours or shorter. Suitable agents are also those with poor oral bioavailability (relative to the bioavailability obtained by injection), wherein the active agent also or alternatively has a bioavailability of less than 20%, such as less than 2%, for example, less than 0.2% or less than 0.1% in an orally administered composition. Suitable active agents according to the present disclosure are those that will benefit from low temperature storage (e.g., refrigeration). Low temperature storage improves the shelf life of preformulations comprising the active agent. The preformulations of the present invention may therefore include "need to be refrigerated" active agents (e.g., as described herein), may benefit from an extended shelf life (e.g., more than 18 months (e.g., 24 months to 5 years) or more than 2 years of shelf life), or may contain at least one volatile component (e.g., a volatile solvent (such as ethanol)). If storage is carried out at refrigeration temperature, such volatile components are more reliably retained in the preformulation during this storage period.

[0111] Where technically feasible, the active agents disclosed herein can also be used in the form of their salts. When a "salt" of an active agent is mentioned herein, this means a pharmaceutically acceptable salt. Such salts are well known in the art and include, for example, chlorides, acetates or pamoates of a base or alkali metal, alkaline earth metal, amino or alkylamino salts of an acid.

[0112] The amount of the bioactive agent to be formulated with the composition of the present disclosure will depend on the functional dose and the period of time during which the reservoir composition formed after administration provides sustained release. Typically, the dose formulated for a particular agent will be approximately equal to the normal daily dose multiplied by the number of days the reservoir provides release. Obviously, this amount will need to be adjusted according to any side effects of a large dose at the beginning of treatment, so this is usually the maximum dose used. In any case, the appropriate precise amount will be easily determined by appropriate experiments.

[0113] In an embodiment, the composition of the present disclosure may include one or more peptide active agents. The peptide active agent may include 5 to 90 or 5 to 60 natural and / or synthetic amino acids (each independently being a D- or L- isomer), especially 5 to 50 or 5 to 40 amino acids. In one embodiment, the active agent is a peptide active agent with no more than 45, such as no more than 30 amino acid residues. In an embodiment, the peptide active agent is a cyclic and / or restricted peptide active agent. The ring size of the cyclic peptide active agent can be 5 to 80 amino acids, for example, 6 to 80 or 8 to 45 or 10 to 35 amino acids.

[0114] Peptide and protein based active agents include human and veterinary drugs selected from the group consisting of adrenocorticotropic hormone (ACTH) and fragments thereof, angiotensin and its related peptides, antibodies and fragments thereof, antigens and fragments thereof, atrial natriuretic peptide, bioadhesive peptides, bradykinin and its related peptides, calcitonin peptides (including calcitonin and amylin and its related peptides), vasoactive intestinal peptide (VIP) (including growth hormone releasing hormone (GHRH), glucagon and secretin), opioid peptides (including pro-opiomelanocortin (POMC) peptides, enkephalin Pentapeptides, dynorphin pro-peptide and related peptides), pancreatic polypeptide-related peptides (such as neuropeptide (NPY), peptide YY (PYY), pancreatic polypeptide (PPY)), cell surface receptor protein fragments, chemotactic peptides, cyclosporin, cytokines, dynorphin and related peptides, endorphin and P-lidotropin fragments, enkephalin and related proteins, enzyme inhibitors, immunostimulatory peptides and polyamino acids, fibronectin fragments and related peptides, gastrointestinal peptides, gonadotropin-releasing hormone (GnRH) agonists and antagonists, glucagon-like peptide 1 and 2, Growth hormone releasing peptide, immunostimulatory peptides, insulin and insulin-like growth factor, interleukin, luteinizing hormone releasing hormone (LHRH) and its related peptides (equivalent to GnRH agonists as described below), melanocortin receptor agonists and antagonists, melanocyte stimulating hormone and its related peptides, nuclear localization signal-related peptides, neurotensin and its related peptides, neurotransmitter peptides, opioid peptides, oxytocin, vasopressin and its related peptides, parathyroid hormone and its fragments, protein kinases and their related peptides, somatostatin and its related peptides, substance P and its related peptides, Transforming growth factor (TGF) and its related peptides, tumor necrosis factor fragments, toxins and toxoids, and functional peptides (such as anti-cancer peptides) (including angiostatin, antihypertensive peptides, anticoagulant peptides and antimicrobial peptides); selected from the group consisting of: proteins such as immunoglobulins, angiogenin, bone morphogenetic protein, chemokine, colony stimulating factor (CSF), cytokine, growth factor, interferon (type I and type II), interleukin, leptin, leukemia inhibitory factor, stem cell factor, transforming growth factor and tumor necrosis factor.An interesting class of bioactive agents suitable for use in the present disclosure are peptide hormones, including those of the following: the glycoprotein hormone family (gonadotropins (LH, FSH, hCG), thyroid stimulating hormone (TSH)); the proopiomelanocortin (POMC) family, adrenocorticotropic hormone (ACTH); posterior pituitary hormones, including vasopressin and oxytocin; the growth hormone family, including growth hormone (GH), human chorionic somatoproteasome (hCS), prolactin (PRL); the pancreatic polypeptide family, including PP, PYY and NPY; melanin concentrating hormone (MCH); orexins; gastrointestinal hormones and peptides, including GLP-1 and GIP; appetite stimulating hormone (ghrelin) and obestatin; adipose tissue hormones and cytokines, including leptin, adiponectin and resistin; natriuretic hormones; parathyroid hormone (PTH); the calcitonin family with calcitonin and amylin; pancreatic hormones, including insulin, glucagon and somatostatin. All synthetic peptides designed to have similar receptor affinity profiles as the above-mentioned peptides are also very suitable for the present disclosure.

[0115] Another significant advantage of the reservoir compositions disclosed herein is that the active agent is gradually released over a long period of time without the need for repeated dosing. Therefore, these compositions are very suitable for situations where patient compliance is difficult, unreliable, or where dosage levels are very important, such as mood-altering active substances, those with a narrow therapeutic window, and those administered to children or to people whose lifestyles are incompatible with a reliable dosing regimen, along with "lifestyle" active substances where the inconvenience of repeated dosing may outweigh the benefits of the active substance. Specific classes of active substances that provide particular advantages in this regard include contraceptives; hormones, including contraceptive hormones, and hormones particularly for children, such as growth hormone; anti-addiction agents; and drugs for treating groups with poor compliance (such as patients with schizophrenia, Alzheimer's disease, or Parkinson's disease); antidepressants and anticonvulsants.

[0116] Cationic peptides and proteins are particularly suitable for certain embodiments. In this embodiment, the peptide or protein can be selected from the group consisting of: octreotide, lanreotide, calcitonin, oxytocin, interferon-β, interferon-γ, interleukin 4, interleukin 5, interleukin 7 or interleukin 8. Other suitable cationic peptides or proteins are those having an isoelectric point above pH 7, such as above pH 8.

[0117] In one aspect, a polar active agent is included in the composition. Particularly suitable polar active agents include peptide and protein actives, oligonucleotides and small water-soluble actives, including those listed above. Of particular interest in this regard are the peptide octreotide and other somatostatin-related peptides, interferon alpha and beta, glucagon-like peptide 1 and glucagon-like peptide 2 receptor agonists, leuprolide and other GnRH agonists, abarelix and other GnRH antagonists, granisetron and ondansetron and other 5-HT3 receptor antagonists.

[0118] GnRH analogs form a class of specific active agents that may be included in the preformulations of the present disclosure. GnRH analogs include synthetic or semisynthetic compounds that interact with the gonadotropin-releasing hormone receptor to trigger its biological response, namely the release of the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH). GnRH analogs include agonists and antagonists of GnRH. Suitable GnRH analogs for the present disclosure include those disclosed in WO 2006 / 075125, the disclosure of which is incorporated herein by reference. Particularly suitable GnRH analogs include those disclosed in the section from page 1, line 33 to page 2, line 29 of WO 2006 / 075125.

[0119] Since GnRH is a peptide hormone, typical GnRH analogs will be peptides, especially peptides with 12 or fewer amino acids. Typically, such peptides will be structurally related to GnRH I, II and / or III and / or one or more known analogs (including those listed herein). The peptides may contain only amino acids selected from the 20 α-amino acids specified in the genetic code, or alternatively may contain their isomers and other natural and non-natural amino acids (usually α, β or γ amino acids) and their analogs and derivatives. Particularly suitable GnRH analogs are restricted peptides with 6 to 12 α-amino acids.

[0120] In one embodiment, the composition comprises a gonadotropin-releasing hormone receptor agonist selected from the group consisting of leuprolide (also known as leuprorelin), goserelin, histrelin, triptorelin, buserelin, deslorelin and nafarelin. In one embodiment of the present disclosure, the preformulation comprises, consists essentially of, or consists of goserelin.

[0121] When present, the GnRH analogue will generally be formulated to comprise 0.02% to 12% by weight of the total composition (based on the amount of free base). Typical values ​​would be 0.1% to 10%, such as 0.2% to 8%, such as 0.5% to 6%, for example 1% to 5%.

[0122] The dosage of the GnRH analogue suitable for inclusion in the composition and the volume of the composition used will depend on the release rate (e.g., controlled by solvent type and dosage) and the release duration as well as the desired treatment level, the activity of the specific agent and the clearance rate of the selected specific active substance. Typically, an amount of 0.1 to 500 mg per dose is suitable for providing a treatment level that lasts for 7 to 180 days. In an embodiment, the dosage of the GnRH analogue in the composition can be 1 to 200 mg. For compositions comprising leuprorelin or goserelin, the level is typically about 1 to 120 mg (e.g., lasting 30 to 180 days). For a reservoir designed to be released within 30 days to 1 year, for example, for a reservoir designed to be released within 3 to 6 months, between injections, the appropriate amount of leuprorelin will be about 0.02 to 1 mg per day. Obviously, the stability of the active substance and the linearity of the release rate will mean that loading may not be a linear relationship with duration. A reservoir administered every 30 days may have, for example, 2 to 30 mg of GnRH analogue. A 90 day depot may have 6 to 90 mg of a GnRH analog, such as one of the GnRH analogs noted herein.

[0123] Somatostatin and somatostatin analogs form another specific class of active agents that may be included in the compositions of the present disclosure. Somatostatin (somatropin release inhibitor, SST) is a natural peptide hormone that is widely distributed in animals, acts as a neurotransmitter in the central nervous system, and has different paracrine / autocrine regulatory effects on several tissues. Two biologically active products are known in higher species, SST-14 and SST-28, the latter being a homologue of SST-14 extended at the N-terminus. SST-14 is a 14-residue cyclic peptide hormone with a disulfide bridge to produce a type II β-turn at a key binding sequence.

[0124] Suitable somatostatins for the present disclosure include endogenous SST-14 and SST-18 and somatostatin analogs, such as those disclosed in WO 2008 / 152401. Since SST-14 is a peptide hormone, somatostatin receptor agonists will generally be peptides, especially peptides with 14 or fewer amino acids. Generally, such peptides will be structurally limited, such as by being cyclic and / or having at least one intramolecular crosslink. Amide, ester or particularly disulfide crosslinks are very suitable. In certain embodiments, somatostatin analogs will exhibit type 2 beta turns. This turn is present in the key region of somatostatin. Peptides may only include amino acids selected from the 20 α-amino acids specified in the genetic code, or may include their isomers and other natural and non-natural amino acids (generally α, β or γ, L- or D-amino acids) and analogs and derivatives thereof.

[0125] Particularly suitable somatostatin analogs for the compositions of the present disclosure include those disclosed in the section from page 20, line 24 to page 21, line 19 of WO 2008 / 152401. In some embodiments, the composition may comprise an endogenous somatostatin or somatostatin analog selected from the group consisting of SST-14, SST-28, octreotide, lanreotide, vapreotide and pasireotide (also known as SOM230) and salts thereof. In some, the somatostatin or somatostatin analog is SST-14 or octreotide and salts thereof.

[0126] When present, the somatostatin receptor agonist will generally be formulated to comprise 0.1% to 12% by weight of the total composition (based on the amount of the free base). Typical values ​​will be 0.1% to 10%, such as 0.5% to 9%, such as 1% to 8%, for example 1% to 7% or 2% to 6%.

[0127] The dosage of the somatostatin receptor agonist suitable for inclusion in the composition and the volume of the composition used will depend on the release rate (e.g., controlled by solvent type and dosage) and the release duration and the desired treatment level, the activity and clearance of the selected specific active substance. Typically, the amount of somatostatin analogs of 1 to 500 mg or 5 to 300 mg per dose is suitable for providing a treatment level that lasts 7 to 90 days. For octreotide, the level is typically about 10 to 180 mg (e.g., lasts 30 to 90 days). Typically, between injections, the amount of octreotide is about 0.2 to 3 mg per day. Therefore, the reservoir used every 30 days will have 6 to 90 mg of octreotide, or the reservoir of 90 days has 18 to 270 mg of octreotide.

[0128] For pasireotide, the dosage will generally be an amount of about 0.05 to 40 mg per week depot duration, such as 0.1 to 20 mg per week (e.g., 1 to 5 mg per week), for 1 to 24 weeks, such as 2 to 16 weeks, for example, 3, 4, 8, 10 or 12 weeks. In an alternative embodiment, the composition can be formulated for weekly administration (e.g., every 7 ± 1 days). The total dose of 0.05 to 250 mg pasireotide per dose is suitable for providing a therapeutic level that lasts 7 to 168 days. In some embodiments, the dosage of pasireotide can be 0.1 to 200 mg, such as 0.2 to 150 mg, for example 0.1 to 100 mg, for example 20 to 160 mg. Obviously, the stability of the active substance and the effect on the release rate will mean that loading and duration may not be a linear relationship. A depot administered every 30 days may have, for example, 0.2 to 20 mg of pasireotide, or a 90-day depot may have 30 to 60 mg of pasireotide.

[0129] In another embodiment, the preformulation comprises an active agent that is not endogenous somatostatin or a somatostatin analog. For example, the peptide active agent may be a peptide that does not interact as an agonist or antagonist at any of the SST(1) to SST(5) receptors (particularly the corresponding human receptors).

[0130] In this alternative embodiment, such preformulation will not contain any somatostatin or somatostatin analog active agent. That is, there is an active agent that does not fall within the scope of the somatostatin analog described in the preceding section. In particular, in this embodiment, the preformulation may contain an active agent that is not selected from endogenous somatostatin, SST-14, SST-28, octreotide, lanreotide, vapreotide or pasireotide or a salt thereof. In addition, in this embodiment, endogenous somatostatin, SST-14, SST-28, octreotide, lanreotide, vapreotide or pasireotide can be completely excluded from the preformulation. In one embodiment, the preformulation does not contain somatostatin, somatostatin receptor agonists and somatostatin analogs.

[0131] Other active agents that may be included in the preformulations of the present disclosure include:

[0132] GnRH antagonists, such as cetrorelix, ganirelix, abarelix, degarelix;

[0133] GLP-1 and its analogs, such as GLP-1(7-37), GLP-1(7-36)amide, liraglutide, semaglutide, exenatide and lixisenatide (AVE0010);

[0134] Glucagon-like peptide 2 agonists (GLP-2) and their analogs, such as GLP-2 and elsiglutide (ZP1846);

[0135] DPPIV inhibitor; sodium / glucose co-transporter 2 (SGLT2) inhibitor.

[0136] Other peptides suitable for use in the present disclosure include: angiopeptides, angiotensin I, II, III, antileukinate, anti-inflammatory peptide 2, aprotinin, bradykinin, bombesin, calcitonin, calcitriol, cholecystokinin (CCK), colony stimulating factor, corticotropin releasing factor, C-peptide, DDAVP, dermatophagnum derived tetrapeptide (TAPS), dynorphin, endorphin, endostatin, endothelin, endothelin-1, enkephalin, epidermal growth factor, erythropoietin, fibroblast growth factor, follicle stimulating hormone, follistatin, follitropin, galanin, galanin-like peptide, galectin-1, gastrin, gastrin releasing peptide, G-CSF, appetite stimulating hormone, Glial-derived neurotrophic factor, GM-CSF, granulocyte colony-stimulating factor, growth hormone, growth hormone-releasing factor, hepatocyte growth factor, insulin, insulin-like growth factor-I and I, interferon, interleukin, leptin, leukemia inhibitory factor, melanocortin 1, 2, 3, 4, melanocyte-stimulating hormone transfer inhibitor, monocyte chemoattractant protein-1 (MCP-1), morphine receptor, NEP1-40, neuropeptide Y, neuropeptide W, orexin A and orexin B, oxytocin p21-Cip1 / WAF-1, TAT fusion protein, parathyroid hormone, pigment epithelium-derived growth factor (PEDF), peptide, peptide, prorenin handle region), peptide YY (3-36), platelet-activating factor, platelet-derived growth factor, prorenin decapeptide, protegrin-1, PR39, prolactin, relaxin, secretin, substance P, tumor necrosis factor, urocortin, vascular endothelial growth factor, vasoactive intestinal polypeptide, vasopressin.

[0137] The short elimination half-life of opioids such as morphine, hydromorphone and oxycodone requires frequent administration of these agents to achieve all-day analgesia, which makes them excellent candidates for long-acting release formulations. Fentanyl and buprenorphine undergo significant first-pass metabolism after oral administration and lack sufficient bioavailability. Together with their high potency, fentanyl and buprenorphine are excellent candidates for long-acting injection reservoir compositions disclosed herein. Sufentanil, remifentanil, oxymorphone, dimorphone, dihydroetorphine, diacetylmorphine are other effective opioid receptor agonists suitable for the present disclosure.

[0138] Buprenorphine is also used for the maintenance treatment of opioid addiction and possibly cocaine and amphetamine and methamphetamine addiction, and the low bioavailability, high variability and limited duration of action of current sublingual buprenorphine preparations lead to problems with unpredictable dose response and withdrawal symptoms, especially in the morning. These problems are effectively solved by using the injection reservoir composition disclosed herein, and the problem of misuse and misleading is solved, wherein the need for high sublingual doses is stripped by injection, and in the case of high sublingual doses, the same dose effect is significantly higher, thus easily leading to the misuse of drugs. Similarly, opioid antagonists can be used to treat addiction using the convenient injection reservoir system provided by the disclosure. The opioid antagonists suitable for the disclosure are naloxone, nalmefene and naltrexone.

[0139] In view of the potential for improving patient's treatment compliance and by providing stable plasma levels over time, antipsychotics including risperidone, iloperidone, paliperidone, olanzapine, asenapine, ziprazidone and aripiprazole are also very suitable for the present disclosure. Similarly, the present disclosure can be used to treat dementia, Alzheimer's disease and Parkinson's disease that have adverse effects on cognition. Suitable active ingredients include donepezil, rivastigmine, galantamine and emantine, rasagilin and pramipexol.

[0140] Another group of active agents that can be included in the preformulations of the present disclosure is a 5HT3 antagonist. 5HT3 antagonists include first and second generation 5HT3 antagonists. In one embodiment, the preformulation comprises a 5HT3 antagonist selected from the group consisting of: ondansetron, tropisetron, granisetron, dolasetron, palonosetron, alosetron, cilansetron and / or ramosetron or a mixture thereof. The dosage of the 5HT3 antagonist suitable for inclusion in the composition and the volume of the preformulation thus used will depend on the release rate (e.g., controlled by solvent type and dosage) and release duration and the desired treatment level, the activity of the specific medicament and the clearance rate of the selected specific active substance. Typically, an amount of 1 to 500 mg per dose is suitable for providing a treatment level that lasts 5 to 90 days. Such an amount can be 1 to 300 mg per dose. For granisetron, this level is generally about 10 to 180mg (for example, continuing 3 days to 60 days).Usually, for the depot designed to release within 30 days to 1 year, such as for the depot designed to release within 3 to 6 months, between injections, the amount of granisetron will be about 0.2 to 3mg per day.Obviously, the linearity of the stability of the active substance and the rate of release will mean that loading and the duration may not be a linear relationship.The depot used in every 30 days may have, for example, 2 to 30mg of active substance, or the depot of 90 days has 6 to 90mg of active substance.

[0141] In embodiments, the active agent is granisetron, buprenorphine, or a mixture of granisetron and buprenorphine, and salts thereof.

[0142] In an embodiment, the composition comprises at least one active agent that is not a somatostatin receptor agonist. In this embodiment, the composition may be completely free of somatostatin receptor agonists. Thus, the composition may be free of active agents that interact as agonists or antagonists at any of the SST(1) to SST(5) receptors (particularly in humans).

[0143] Other optional components

[0144] In one embodiment, the preformulation comprises at least 10ppm EDTA. Suitable preformulations comprising, for example, amines (such as ethanolamine and EDTA) are described in WO 2018 / 060212 (especially page 18 to page 21), and its complete file is incorporated herein by reference. Suitable EDTA salts enabling the presence of EDTA in the preformulation include EDTA salts of tetra(ethanolammonium) EDTA or ethanolamine, diethanolamine, meglumine, trihydroxymethylamine, ethylenediamine and / or serinol.

[0145] Application

[0146] The preformulations disclosed herein are typically formulated for parenteral administration, e.g., by subcutaneous injection. Such administration is typically not an intravascular method, but rather subcutaneous (sc), intracavitary, or intramuscular (im). Typically, administration will be by injection, a term used herein to denote any method of passing a formulation through the skin, such as by a needle, catheter, or needle-less or needle-free injector.

[0147] Preferred parenteral administration is by im or sc injection, most preferably by sc injection.An important feature of the composition disclosed herein is that it can be administered by both im and sc and other routes of non-toxic or significant local effects.It is also suitable for intracavitary administration.The advantage of deep sc injection is that, compared with (deep) im injection for some current depots, the depth to the subject is smaller and the pain level is lower, and it is technically most suitable for the current situation because it combines the simplicity of injection with the low risk of local side effects.Unexpectedly, the inventors observed that the formulation provides the sustained release of the active agent in a predictable period of time by both subcutaneous and intramuscular injections.Therefore, this allows the injection site to vary widely, and allows the administration of dosage without considering the tissue depth at the injection site in detail.

[0148] In one embodiment applicable to all aspects of the present disclosure, the preformulation disclosed herein can be administered by an automatic injection device, such as an automatic syringe, which generally comprises a prefilled glass syringe or glass barrel (e.g., a glass syringe or barrel) (provided that the inner surface does not contain a pre-applied silicone lubricant), a mechanical or electrical device for expelling the formulation (e.g., a spring or other elastic material in tension or compression or a battery-powered electric motor), a trigger or switch for initiating the injection, and a needle to achieve the injection. Such an automatic syringe filled with any formulation of the present disclosure will obviously form another aspect.

[0149] The preferred lipid preformulation of the present disclosure provides non-lamellar liquid crystal depot compositions (especially in vivo) after being exposed to aqueous fluid.As used herein, term "non-lamellar" is used to represent normal phase or reverse phase liquid crystal phase (such as cubic phase or hexagonal phase) or L3 phase or any combination thereof.Term liquid crystal represents all hexagonal, all cubic liquid crystal phases and / or all mixtures thereof.Unless otherwise indicated, hexagonal as used herein represents "forward" or "reverse" hexagonal (preferably reverse) phase, and "cubic" represents any cubic liquid crystal phase.By referring to description and example provided herein and WO2005 / 117830, it is not difficult for technical personnel to determine those compositions with suitable phase behavior, but the most favorable composition region for phase behavior is component i): the ratio of phospholipid is in the region of 40:60 to 70:30, preferably 45:55 to 55:45, more preferably 40:60 to 54:46. A ratio of around 50:50 (eg, ±2) is very preferred, and around 50:50 is most preferred.

[0150] It is important to understand that the preformulations disclosed herein have low viscosity (e.g., as discussed herein). Therefore, these preformulations must not be in any bulk liquid crystalline phase, because the viscosity of all liquid crystalline phases is significantly higher than the viscosity that can be applied by a syringe or similar injection dispenser. The preformulations disclosed herein will therefore be in a non-liquid crystalline state, such as a solution, L2 or L3 phase, particularly a solution or L2. As used throughout this article, the L2 phase is preferably a "swollen" L2 phase, which contains more than 5wt%, preferably more than 7%, and most preferably more than 9% of an organic monohydric alcohol solvent with a viscosity-reducing effect. The preformulations disclosed herein in the L2 phase form a group of preferred preformulations, and these preformulations typically contain at least 2% water as a polar solvent.

[0151] As used herein, the term "low viscosity mixture" is used to represent a mixture that can be easily applied to a subject and is particularly easily applied by a standard syringe and needle device. This can be represented, for example, by the ability to be dispensed from a 1ml disposable syringe through a small gauge needle. Preferably, the low viscosity mixture can be dispensed by manual pressure through a 19-gauge needle, preferably less than 19, such as a 22G (22), more preferably a 23G (optionally even 25 or 27 or 29) needle. In a particularly preferred embodiment, the low viscosity mixture should be a mixture that can pass through a standard sterile filtration membrane (such as a 0.22 μm syringe filter). The typical range of suitable viscosity will be, for example, 1 to 1000 mPas at 25 ° C or other viscosities discussed herein. Suitable viscosity ranges include 200-600 mPas at 25 ° C or 300-500 mPas at 25 ° C. Thin-wall (TW), extra-thin wall (ETW), and ultra-thin wall (UTW) needles are typically used in embodiments applicable to all aspects of the present disclosure. Suitable needles include 22G UTW and 23G TW.

[0152] It has been observed that by adding a small amount of low-viscosity organic monohydric alcohol solvent (as indicated herein), a very significant viscosity change can be provided. For example, only adding 5% solvent in the lipid mixture can reduce the viscosity by 100 times, and adding 10% solvent can reduce the viscosity by up to 10,000 times. In order to achieve this nonlinear, synergistic effect in reducing viscosity, it is important to use solvents with suitable low viscosity and suitable polarity. Such solvents include those described below. Preferred low-viscosity mixtures include molecular solutions, including dispersions of peptide active agents in molecular solutions with other components.

[0153] After application, the preferred lipid-based preformulation of the disclosure undergoes a phase structure transition from a low-viscosity mixture to a high-viscosity (generally tissue-adhesive) reservoir composition. Typically, this will be a transition from a molecular mixture, a swollen L2 and / or L3 phase to one or more (high-viscosity) liquid crystalline phases (such as a forward or reverse hexagonal or cubic liquid crystalline phase or its mixture). Further phase transitions may also occur after application. Obviously, complete phase transition is not necessary for the function of the disclosure, but at least the surface layer of the applied mixture will form a liquid crystalline structure. Typically, for at least the surface area of ​​the applied preparation (the part is in direct contact with air, body surface and / or body fluid), this transition will be fast. This will most preferably be in a few seconds or minutes (for example, from 1 second to up to 30 minutes, preferably up to 10 minutes, more preferably 5 minutes or shorter time). The remainder of the composition can be more slowly phase transitioned to a liquid crystalline phase by diffusion and / or as the dispersion of the surface area.

[0154] Without being bound by theory, it is believed that after being exposed to excess aqueous fluid, the preformulation of the present disclosure loses some or all of the organic solvents contained therein (e.g., by diffusion) and absorbs aqueous fluid from the body environment (e.g., in vivo environment). For lipid preformulations, at least a portion of the preparation preferably produces a non-lamellar, particularly liquid crystalline phase structure. In most cases, these non-lamellar structures are very viscous and are not easily dissolved or dispersed into the in vivo environment. The result is that an overall "depot" is produced in vivo, with only limited areas exposed to body fluids. In addition, because the non-lamellar structure has large polarity, non-polarity and border regions, the lipid depot is very effective in dissolving and stabilizing active agents such as peptides and protecting them from degradation mechanisms. As the depot composition formed by the preformulation gradually degrades over a period of days, weeks or months, the active agent is gradually released and / or diffused from the composition. Because the environment in the depot composition is relatively protected, the preformulation of the present disclosure is very suitable for active agents with relatively low biological half-life (see above).

[0155] By incorporating at least 10% of a polar solvent (particularly at least 5% of water) into the preformulation, it is believed that the rate of phase transition to a non-lamellar (e.g., liquid crystalline) phase at the surface of the injected preformulation can be enhanced compared to compositions comprising an organic solvent in the substantial absence of water. The properties of the resulting reservoir are thus improved, and further control of the release of the active agent is achieved.

[0156] The reservoir system formed by the formulation of the present disclosure is very effective in protecting the active agent from degradation, thus allowing an extended release period. Therefore, the formulation of the present disclosure can provide an in vivo reservoir of the peptide active agent, which only needs to be applied once every 5 to 90 days, preferably 5 to 60 days, and more preferably 6 to 32 days. Obviously, a longer stable release period is desirable for the comfort and compliance of the patient, and requires less time for health professionals (in the case of being unable to self-administer the composition). In the case of self-administering the composition, patient compliance can be helped by weekly (e.g., every 7 days, optionally ± 1 day) or monthly (e.g., every 28 days or 30 days (optionally ± 7 days) administration, so as not to forget the need for administration.

[0157] The significant advantage of the depot precursors disclosed herein is that they are stable homogeneous phases. That is, they can be stored at room temperature or refrigerator temperature for a considerable period of time (preferably at least 6 months) without phase separation. In addition to providing favorable storage and convenient administration, this also allows the dose of a peptide active agent (e.g., somatostatin analogs, e.g., octreotide) to be selected by injecting a selected volume, by reference to the species, age, sex, weight and / or physical condition of an individual subject.

[0158] Thus, the present disclosure provides methods including selecting an individual-specific (particularly by subject weight) dosage amount. This method of dose selection is the selection of administration volume.

[0159] The preformulations disclosed herein are very advantageous because they are stable for long-term storage in their final "administration-ready" form. Thus, they can be easily supplied for administration by a health professional or a patient or their caregiver, who need not be a fully trained health professional and may not have the experience or skills to prepare complex formulations. This is particularly important in diseases of long duration and slow effects such as diabetes.

[0160] The amount of the lipid component in a lipid-based preformulation is typically at least 40% (eg, 40% to 95%, such as 50% to 90% or 50% to 80%) by weight of the total formulation.

[0161] As used herein, the terms "long-standing precipitates" and "visible precipitates" are used to refer to insoluble precipitates (e.g., particles) in a preformulation (e.g., a lipid-based preformulation in a glass syringe or glass barrel) that do not re-dissolve when the preformulation is equilibrated at room temperature (15°C-25°C, e.g., 25°C) for a period of at least 15 minutes (e.g., at least 30 minutes or at least 1 hour (e.g., 1 to 24 hours)). The term "refrigerated conditions" is used to refer to a temperature from 0°C to 10°C, such as a temperature from 2°C to 8°C. Injectable formulations (e.g., parenteral formulations, e.g., lipid-based preformulations as described herein) are facing regulatory requirements, and the presence of particles / precipitates in formulations for parenteral (e.g., subcutaneous administration) is regulated by agencies. The glass syringe or glass barrel containing the lipid-based preformulation described herein is described as being (substantially) free of visible precipitates and / or turbidity (clear liquid), which can be determined according to USP <790> In addition, the container (syringe or barrel) containing the lipid-based preformulation as disclosed herein contains no more than (NMT) 6000 particles (precipitate and / or turbidity) greater than or equal to 10 μm and / or NMT 600 particles (precipitate and / or turbidity) greater than or equal to 25 μm, as determined by USP <788> Determined by USP <788> , particles are to be understood as "particulate matter in injectable and parenteral solutions consisting of mobile, undissolved particles (other than gas bubbles) that are unintentionally present in solution", i.e., USP <788> Suitable for the detection and quantification of sediment and / or turbidity. Throughout this specification and the appended claims, it should be understood that USP <788> Alternative USP <790> or in combination with (USP <788> The European alternative is Ph. Eur. 2.9.19. Testing of containers can be performed using Method 1 (Light Obscuration Test) and if such containers do not meet the specification, the test can be repeated using Method 2 (Microscopic Particle Count).

[0162] The term "the glass syringe or glass barrel containing the lipid-based preformulation is substantially free of visible precipitates" and the use of the term "clear" is to be understood that the preformulation is acceptable for parenteral (such as subcutaneous) injection in a subject.

[0163] Uses of diacylglycerol compositions

[0164] In one aspect, the present disclosure provides use of a diacylglycerol composition having a fatty acid composition of at least 98% oleic acid (18:1) as determined according to Ph. Eur. 9.0, Method C, 2.4.22 (determination of fatty acid composition by gas chromatography) in preventing or reducing the formation of long-lived precipitates in a preformulation comprising i) a diacylglycerol composition according to the first aspect of the present disclosure and ii) at least one biocompatible organic solvent.

[0165] In one embodiment, the use relates to the use of a diacylglycerol composition, wherein the diacylglycerol composition according to the first aspect of the present disclosure is the only diacylglycerol present in the preformulation, i.e. the preformulation is substantially free of any diacylglycerol composition other than the diacylglycerol composition according to the first aspect of the present disclosure.

[0166] The biocompatible organic solvent component ii) is the same as the component ii) of the preformulation according to the first aspect of the present disclosure. Therefore, the biocompatible organic solvent component ii) in the use of the present disclosure can be the same as any embodiment described with respect to the biocompatible organic solvent component ii) of the preformulation according to the present disclosure.

[0167] In one embodiment, the use of the diacylglycerol composition of the present disclosure is to prevent or reduce the formation of long-lived precipitates in the preformulation when the preformulation is stored at a temperature of 0°C to 10°C, such as 2°C to 8°C, for a period of at least 24 hours, such as at least 1 month, such as at least 3 months, such as at least 6 months (e.g., 6 months to 3 years). Such "refrigerated" periods and conditions apply to all aspects that the context permits.

[0168] As used herein, the terms "long-standing precipitate", "precipitate", "turbidity", "opalescence" are used to refer to changes in a preformulation, for example, a precipitate that does not redissolve when the preformulation is equilibrated / reconditioned at room temperature (e.g., 25° C.) for a period of at least one hour (e.g., 1 to 24 hours) after refrigeration. An alternative reconditioning method is to warm the prefilled syringe with the aid of body temperature (e.g., by contact with the human body, such as holding the syringe in the hand) for a time sufficient for reconditioning, for example, 1 to 10 minutes before administration, or any suitable method that does not negatively affect the active agent and / or the lipid-based formulation. Reconditioning prior to administration (injection) typically also includes rotating the prefilled syringe containing the lipid-based composition described herein in the hand through an arc of about 45° to 180° for 5 to 50 times (e.g., about 10 to 20 times).

[0169] In another aspect, the present disclosure provides a method for preventing or reducing the formation of long-lived precipitates in a preformulation when the preformulation is stored at a temperature of 0°C to 10°C, such as 2°C to 8°C, for a period of at least 24 hours, such as at least 1 month, such as at least 3 months, such as at least 6 months (e.g., 6 months to 3 years), the preformulation comprising: (i) a diacylglycerol composition; and (ii) at least one biocompatible organic solvent; the method comprising forming the preformulation with the diacylglycerol composition according to the first aspect of the present disclosure. In particular, the use described is in a preformulation as described herein in combination with a glass syringe or glass barrel that does not contain a silicone lubricant.

[0170] Pre-filled glass syringe

[0171] On the one hand, present disclosure provides a kind of pre-filled glass syringe, it is pre-filled with lipid-based formulation (as described in any embodiment of this paper) and comprises the syringe barrel with inner surface, wherein the inner surface portion of the syringe barrel that is always in contact with the formulation based on lipid does not contain any pre-applied silicone lubricant.Unexpectedly, the inventor has determined that when preparing the pre-filled glass syringe pre-filled with lipid-based formulation (wherein the inner surface portion of the syringe barrel that is always in contact with the composition based on lipid is substantially free of any pre-applied lubricant), it is prevented from forming a long-standing precipitate in the formulation based on lipid after storage under refrigerated conditions.The substitute of the pre-filled glass syringe is a pre-filled glass barrel, for example, suitable for automatic syringes, such as pens.

[0172] As used herein, the term "lipid-based formulation" means any formulation comprising a lipid component. In one embodiment, the lipid-based formulation comprises diacyl lipids. In one embodiment, the lipid-based formulation comprises diacylglycerols, whose fatty acid composition is at least 98% oleic acid (18: 1), as determined according to Method C, 2.4.22 (determination of fatty acid composition by gas chromatography) of European Pharmacopoeia 9.0. In one embodiment, the lipid-based formulation forms or is capable of forming at least one liquid crystalline phase structure after contact with an excess of aqueous fluid. In one embodiment, the lipid-based formulation is a preformulation according to the second aspect of the present disclosure (as described in any embodiment herein).

[0173] In one embodiment, the prefilled glass syringe comprises a lipid-based formulation containing an active agent. In one embodiment, the active agent is an active agent that requires refrigeration. In one embodiment, the active agent is a peptide active agent, for example, a peptide active agent having no more than 45, such as no more than 30 amino acid residues. In one embodiment, the active agent is a cyclic and / or restricted peptide active agent. In one embodiment, the active agent is somatostatin or a somatostatin analog, such as a somatostatin or a somatostatin analog selected from the group consisting of SST-14, SST-28, octreotide, lanreotide, pasireotide and vapreotide or its salt. In one embodiment, the active agent is octreotide or its salt, preferably octreotide chloride.

[0174] As used herein, a surface that is "substantially free" of any pre-applied lubricant refers to a surface that is covered by less than 1% area (e.g., 1% or 0.000%), preferably less than 0.1% area, and most preferably less than 0.01% area by any pre-applied lubricant.

[0175] In one embodiment, the portion of the interior surface of the syringe barrel that is in constant contact with the lipid-based formulation is substantially free of any pre-applied silicone lubricant.

[0176] The pre-filled glass syringes of the present disclosure have surprisingly low break-out forces. Break-out force is the maximum force required to initiate movement of a syringe plunger against the syringe barrel. It represents the force required to overcome the static friction between the syringe plunger and the syringe barrel and is therefore a measure of the ease with which a composition can be injected.

[0177] In one embodiment, the prefilled glass syringe has a break-away force of no more than 35 N, preferably no more than 30 N, preferably no more than 25 N, preferably no more than 20 N, preferably no more than 15 N, preferably no more than 10 N.

[0178] Without being bound by theory, it is believed that the lipid-based formulation provides sufficient lubrication to allow the pre-filled syringe to be operated without undue force without the need for a lubricant.

[0179] "Pre-applied lubricant" as referred to herein is any lubricant commonly applied to glass syringes to allow them to run smoothly and tolerably low friction. Such lubricants are well known in the art. Examples may include petroleum-based lubricants or silicone lubricants.

[0180] Pharmaceutical products

[0181] As described herein, new treatment options using long-term release (extended release, etc.) drug products are needed. An example of such a drug product is a glass syringe or glass barrel containing a lipid-based preformulation, wherein at least the inner surface of the glass syringe is in contact with the lipid-based preformulation and the inner surface does not contain a pre-applied silicone lubricant, and wherein the lipid-based preformulation comprises

[0182] a) 20-80 wt% of diacylglycerols whose fatty acid composition is at least 98% oleic acid (18:1) as determined according to Ph. Eur. 9.0, Method C, 2.4.22 (Fatty acid composition by gas chromatography);

[0183] b) 20-80 wt% of phospholipids;

[0184] c) 1-30 wt % of a solvent;

[0185] d) biologically active agents (e.g., requiring storage at temperatures below 10°C);

[0186] wherein a) and b) account for at least 94 wt% of the total lipid content of the lipid-based preformulation, and the lipid-based preformulation is a clear liquid (e.g., free of turbidity or haze) having a viscosity of less than 1000 mPas at 20°C and is substantially free of visible precipitate after storage at a temperature of less than or equal to 10°C, such as 0°C-10°C, such as 2°C-8°C, for at least 1 month followed by equilibration at room temperature for a period of at least one hour, as described in accordance with USP <790> and / or USP <788> Determined.

[0187] When assembled into a drug product (i.e., a glass syringe or glass barrel containing a preformulation as described herein), the various components (e.g., the glass syringe described herein, the preformulation, the optional stopper) are capable of long-term storage of active agents for which low temperature storage (such as above freezing and up to 10°C) is necessary or desirable in order to achieve sufficient long-term stability, e.g., at least one year or longer, thereby enabling goals that cannot be achieved by the individual components alone. The complexity of the lipid-based preformulations disclosed herein, the interaction with glass surfaces (particularly pre-applied silicone lubricants), the injectability (e.g., injection force, release force, etc.), etc., which are required to provide safe and effective administration of lipid-based preformulations containing one or more active agents for long-term release therapy, have proven to be challenging, particularly in view of the need to provide a liquid preformulation (including an active agent) that is free of precipitates and free of turbidity and / or opalescence. Thus, the glass syringes or glass barrels and combinations of various aspects and embodiments disclosed herein enable providing one or more drug products suitable for refrigerated storage and providing lipid-based long-acting therapies (e.g., long duration) comprising active agents that require refrigeration.

[0188] List of Examples

[0189] E1) A diacylglycerol composition comprising at least 97.0 wt%, such as at least 97.5 wt%, such as at least 98.0 wt%, such as at least 98.5 wt% of diacylglycerols having two fatty acid residues, each independently having 16-20 carbon atoms and one or two carbon-carbon double bonds.

[0190] E2) A diacylglycerol composition according to E1, wherein the composition comprises less than 3 wt% of saturated fatty acid residues as measured by gas chromatography (GC).

[0191] E3) A diacylglycerol composition according to E1, comprising less than 2 wt%, such as less than 1 wt%, of saturated fatty acid residues as measured by gas chromatography (GC).

[0192] E4) A diacylglycerol composition according to E2 or E3, wherein the amount of saturated fatty acid residues in the composition is calculated according to European Pharmacopoeia 9.0, Method C, 2.4.22 (Fatty acid composition by gas chromatography).

[0193] E5) The diacylglycerol composition according to E1-E4, wherein the diacylglycerol is a mixture of 1,2-diacylglycerol and 1,3-diacylglycerol.

[0194] E6) The diacylglycerol composition according to E5, wherein the isomer ratio of 1,2-diacylglycerol to 1,3-diacylglycerol is between 5:1 and 1:5, such as between 4:1 and 1:4, such as between 1:1.5 and 1:3.5.

[0195] E7) The diacylglycerol composition according to E1-E6, wherein the diacylglycerol is diolein.

[0196] E8) A diacylglycerol composition according to E1-E7, comprising no more than 2 wt%, such as no more than 1.5 wt%, such as no more than 1 wt%, such as no more than 0.5 wt% of monoacylglycerol.

[0197] E9) A diacylglycerol composition according to E1-E8, comprising no more than 2.5 wt%, such as no more than 2 wt%, such as no more than 1.5 wt% triacylglycerols.

[0198] E10) A preformulation comprising:

[0199] i) a diacylglycerol composition according to any one of the preceding claims; and

[0200] ii) at least one biocompatible organic solvent;

[0201] wherein the preformulation forms or is capable of forming at least one liquid crystalline phase structure upon contact with an excess of an aqueous fluid.

[0202] E11) A preformulation according to E10, wherein the diacylglycerol composition according to any one of E1 to E9 is the only diacylglycerols in the preformulation.

[0203] E12) The preformulation according to E10 or E11, wherein the at least one biocompatible organic solvent is a biocompatible oxygenated organic solvent; such as a solvent selected from the group consisting of ethanol, N-methylpyrrolidone (NMP), propylene glycol, benzyl alcohol, DMSO and mixtures thereof.

[0204] E13) Preformulation according to any one of E10-E12, further comprising at least one phospholipid.

[0205] E14) Preformulation according to E13, wherein the at least one phospholipid is selected from the group consisting of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI) and mixtures thereof.

[0206] E15) Preformulation according to E13 or E14, wherein the at least one phospholipid comprises or consists of phosphatidylcholine.

[0207] E16) Preformulation according to any of E13-E15, wherein the ratio of diacylglycerols to phospholipids is in the range of 20:80 to 80:20, such as 60:40 to 40:60.

[0208] E17) The preformulation according to any one of E10-E16, further comprising a biologically active agent.

[0209] E18) The preformulation according to E17, wherein the bioactive agent requires refrigeration or the bioactive agent requires refrigeration.

[0210] E19) Preformulation according to E17 or E18, wherein the biologically active agent is a peptide active agent, for example a peptide active agent having no more than 45, such as no more than 30 amino acid residues.

[0211] E20) The preformulation according to E19, wherein the peptide active agent is a cyclic and / or constrained peptide active agent.

[0212] E21) Preformulation according to E17 to E20, wherein the biologically active agent is somatostatin or a somatostatin analogue, such as a somatostatin or a somatostatin analogue selected from the group consisting of SST-14, SST-28, octreotide, lanreotide, pasireotide and vapreotide or a salt thereof.

[0213] E22) Preformulation according to E17 to E20, wherein the biologically active agent is octreotide.

[0214] E23) The preformulation according to E17 to E20, wherein the bioactive agent is SST-14.

[0215] E24) Preformulation according to E10 to E23, further comprising an alkylammonium salt of EDTA.

[0216] E25) Use of the diacylglycerol composition according to any one of E1 to E9 for preventing or reducing the formation of long-lived precipitates in a preformulation, the preformulation comprising:

[0217] (i) a diacylglycerol composition according to any one of E1 to E9, and

[0218] (ii) at least one biocompatible organic solvent.

[0219] E26) Use according to E23, wherein the preformulation is substantially free of any diacylglycerol composition other than the diacylglycerol composition according to any one of E1 to E9.

[0220] E27) The use according to E25 or E26, for preventing or reducing the formation of long-lasting precipitates in the preformulation when the preformulation is stored at a temperature of 0°C to 10°C, such as 2°C to 8°C, for a period of at least 24 hours, such as at least 1 month, such as at least 3 months, such as at least 6 months.

[0221] E28) Use according to E25 to E27, wherein the long-standing precipitates do not redissolve when the preformulation is equilibrated at room temperature for a period of one hour.

[0222] E29) A method for preventing or reducing the formation of long-lived precipitates in a preformulation when the preformulation is stored at a temperature of 0°C to 10°C, such as 2°C to 8°C, for a period of at least 24 hours, such as at least 1 month, such as at least 3 months, such as at least 6 months, the preformulation comprising:

[0223] (i) a diacylglycerol composition; and

[0224] (ii) at least one biocompatible organic solvent;

[0225] The method comprises forming the preformulation with the diacylglycerol composition according to any one of E1 to E9.

[0226] E30) The method according to E29, wherein the preformulation is formed with the diacylglycerol composition according to any one of E1 to E9 as the only diacylglycerols in the preformulation.

[0227] E31) A method according to E29 or E30, wherein the long-standing precipitates do not redissolve when the preformulation is equilibrated at room temperature for a period of one hour.

[0228] E32) A prefilled container comprising a glass cylinder and a stopper, wherein a volume is defined by the space bounded by the glass cylinder and the stopper, and wherein the volume is at least partially filled with the preformulation according to E10 to E24.

[0229] E33) The prefilled container according to E32, which is a prefilled syringe or a prefilled cartridge.

[0230] E34) A prefilled glass syringe, prefilled with a lipid-based formulation and comprising a syringe barrel having an inner surface, wherein the portion of the inner surface of the syringe barrel that is in constant contact with the lipid-based formulation is substantially free of any pre-applied lubricant.

[0231] E35) The prefilled glass syringe according to E34, wherein the portion of the inner surface of the syringe barrel that is in contact with the lipid-based formulation at all times prior to use is substantially free of any pre-applied silicone lubricant.

[0232] E36) The prefilled glass syringe according to E34 or E35, wherein the lipid-based formulation forms or is capable of forming at least one liquid crystalline phase structure upon contact with an excess of an aqueous fluid.

[0233] E37) The prefilled glass syringe according to any one of E34 to E36, wherein the lipid-based formulation comprises a diacyl lipid.

[0234] E38) The prefilled glass syringe according to any one of E34 to E37, wherein the lipid-based formulation comprises diacylglycerols.

[0235] E39) The prefilled glass syringe according to any one of E34 to E39, wherein the lipid-based formulation comprises the diacylglycerol composition according to any one of E1 to E9.

[0236] E40) The prefilled glass syringe according to any one of E34 to E40, wherein the lipid-based formulation further comprises a bioactive agent.

[0237] E41) The prefilled glass syringe according to E40, wherein the bioactive agent requires refrigeration.

[0238] E42) A prefilled glass syringe according to E40 or E41, wherein the biologically active agent is a peptide active agent, for example a peptide active agent having no more than 45, such as no more than 30 amino acid residues.

[0239] E43) The prefilled glass syringe according to E42, wherein the peptide active agent is a cyclic and / or restricted peptide active agent.

[0240] E44) The prefilled glass syringe according to E40 to E43, wherein the bioactive agent is somatostatin or a somatostatin analogue, such as a somatostatin or a somatostatin analogue selected from the group consisting of SST-14, SST-28, octreotide, lanreotide, pasireotide and vapreotide or a salt thereof.

[0241] E45) The prefilled glass syringe according to E40 to E44, wherein the biologically active agent is octreotide or a salt thereof, preferably octreotide chloride.

[0242] E46) The prefilled glass syringe according to any one of E40 to E45, wherein the lipid-based formulation is a preformulation according to any one of E10 to E24.

[0243] E47) A prefilled glass syringe according to any one of E40 to E46, having a break-away force of no more than 35 N, such as no more than 30 N, no more than 25 N, no more than 20 N, no more than 15 N, no more than 10 N or no more than 5 N.

[0244] E48) The prefilled glass syringe according to any one of E40 to E46, having a break-away force between 5 and 25N.

[0245] E49) A prefilled glass syringe according to any one of E40 to E48, having a sliding force of no more than 35N, such as no more than 30N, no more than 25N, no more than 20N, no more than 15N, no more than 10N or no more than 5N.

[0246] E50) A method of administering a preformulation according to any one of E10 to E24 to a patient in need thereof, wherein the syringe containing the preformulation is maintained at 2°C to 8°C until about 1 h before administration and allowed to equilibrate at room temperature for about 1 hour before administration.

[0247] E51) The method according to E50, wherein the preformulation has no visible turbidity upon application.

[0248] E52) The method according to E50 or E51, wherein the syringe is warmed at body temperature (eg, by contact with the human body, such as by holding in the hand) for 1 to 10 minutes before administration.

[0249] E53) The method according to any one of E49 to E52, wherein the syringe is rotated in the hand through an arc of about 45 to 180° 5 to 50 times (e.g., about 10 to 20 times) before administration.

[0250] E54) A method according to any one of E49 to E53, wherein the syringe is a prefilled glass syringe according to any one of E34 to E48.

[0251] Examples

[0252] Material

[0253] All materials used in the examples were obtained from commercial sources and were of pharmacopoeial grade or the highest purity grade available where applicable. The following abbreviations are used throughout the examples:

[0254] EtOH Ethanol (99.7% European Pharmacopoeia)

[0255] GDO diolein (Cithrol GDO HP-SO-(LK) from Croda)

[0256] OCT(Cl) Octreotide Hydrochloride

[0257] PG Propylene glycol (European Pharmacopoeia)

[0258] SPC Soy Phosphatidylcholine (from Phosphatidylcholine S100 from Phosphatidylcholine Corporation)

[0259] General Procedures

[0260] Preparation of 1,3-dioleylglycerol (1,3GDO)

[0261]

[0262] Solution 1

[0263] 1 equivalent of oleic acid (99% purity) was dissolved in dichloromethane and maintained under an inert atmosphere (N2) at about 23°C. When 1.5 equivalents of oxalyl chloride were added dropwise, the temperature was raised to 15°C and maintained between 15°C and 20°C for 25 min. The mixture was stirred overnight under an inert atmosphere. The solvent and excess oxalyl chloride were removed and the remaining residue was added to a stirred inert (N2) dichloromethane suspension containing 0.45 equivalents of dimerized 1,3-dihydroxypropane-2-one, 0.5 equivalents of pyridine, 0.25 equivalents of DMAP. The reaction mixture was maintained at 20°C for 15h, then the formed pyridine hydrochloride was removed by filtration and washed with dichloromethane. The combined organics were washed with 5% sodium chloride, 5% sodium carbonate, 0.1M hydrochloric acid, and then 5% sodium chloride. The solution was dried and evaporated to give a semisolid, which was triturated with methanol and then refrigerated overnight. The collected solid was recrystallized from isopropyl ether and methanol to give 2-oxopropane-1,3-dioleic acid diester (98.5% purity by HPLC).

[0264] The obtained 2-oxopropane-1,3-dioleic acid diester was dissolved in 500ml tetrahydrofuran, and after the stepwise addition of sodium borohydride, 20ml water was added, then cooled to 5°C, and the temperature was kept at about 5°C-10°C. The reaction was monitored by HPLC, and after the reaction was completed, the addition of sodium borohydride was stopped, the solvent was removed, and the residue was distributed between ethyl acetate and water. The aqueous phase was re-extracted with ethyl acetate, and the combined organic matter was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized twice from hexane to obtain 1,3-dioleyl glyceride (HPLC purity of 98.5%).

[0265] Isomerization of 1,3 GDO

[0266] The obtained 1,3-diolein is converted to a mixture of 1,2-diolein and 1,3-diolein by diluting 1,3-diolein with about 75 vol% ethanol in the presence of a protic solvent and heating the mixture to about 70°C for 24 hours to reach a ratio of about 1.9 (1,3-GDO / 1,2-GDO). Optionally, 1,3-diolein is allowed to reach equilibrium within 4 days in the presence of 50% ethanol and at 40°C.

[0267] The mixture of 1,2-diolein and 1,3-diolein obtained has a purity of 98% and does not exceed (NMT) 2% (area) of unsaturated fatty acids (sum of C18:2, C18:3 and C20:1) and contains NMT 1% (area) of saturated fatty acids (sum of C16:0, C18:0 and C20:0), as determined according to European Pharmacopoeia 9.0, method C, 2.4.22. (determination of fatty acid composition by GC) (expressed as percentage of the peak area of ​​the corresponding methyl esters), i.e. the fatty acid composition contains at least 98% oleic acid (18:1).

[0268] Example 1: Storage stability of preformulations containing diacylglycerol compositions

[0269] The lipid stock solution is prepared by weighing in a mixture of soybean phosphatidylcholine (SPC), 1,2-dioleylglycerol and 1,3-dioleylglycerol (GDO) prepared as above, ethanol (EtOH) and propylene glycol (PG), and it is mixed upside down until uniform. The lipid stock solution is added to the weighed octreotide chloride (OCT (Cl)) powder, and then the vial is flushed with nitrogen and mixed upside down until uniform to prepare the final formulation. The formulation is then sterile filtered with 3 bar pressure, then divided into vials, and finally flushed with nitrogen. The filling of the pre-filled syringe is carried out by adding about 0.5g formulation to each syringe using a disposable pipette under ambient air and temperature conditions. With the aid of a metal wire, a plunger rod (which is subsequently separated) is used to put a stopper (e.g., a commercially available stopper from BD or West) in place. Reduce the bubbles (air) in the syringe as much as possible. The syringe is then placed in a climate chamber, and samples are extracted at a specified time point for visual inspection and HPLC analysis. All syringes were pre-lubricated with silicone oil, e.g., commercially available 1 mL glass syringes such as those sold by Gerresheimer, Schott, and BD. Comparative compositions were prepared as above, except that GDO from a commercial source (Cithrol GDO HP-SO-(LK) from Croda) was used instead of the disclosed GDO prepared as above.

[0270] Additionally, samples (3-10) were prepared using a similar procedure (but including other excipients and optionally excluding the active agent (octreotide chloride)) and are included in Table 1.

[0271] Table 1: Composition (wt%)

[0272]

[0273] *contrast

[0274] **Fatty acid composition containing at least 98% oleic acid (18:1)

[0275] The samples were stored under refrigerated conditions of 2°C-8°C, 15°C, 25°C / 60%RH, and 40°C / 75%RH.

[0276] Extracts were taken from samples 1-10 at day 0, after 1 month, 3 months, 6 months, 12 months and 14 months. The extracts from samples stored at 15°C, 25°C / 60%RH, 40°C / 75%RH remained clean and uniform throughout the test period. Extracts from samples stored at 2°C-8°C were frequently frozen and inspected visually and under polarized light. The inspection results from samples stored under refrigerated conditions are presented in Table 2.

[0277] Table 2:

[0278] Sample No.: Day 0 1 month 3 months 6 months 12 months 14 months 1* qualified qualified fail fail fail fail 2 qualified qualified qualified qualified qualified qualified 3* qualified qualified fail fail fail fail 4 qualified qualified qualified qualified qualified qualified 5* qualified fail fail fail fail fail 6 qualified fail fail fail fail fail 7* qualified qualified qualified qualified fail fail 8 qualified qualified qualified qualified qualified qualified 9* qualified qualified fail fail fail fail 10 qualified qualified qualified qualified qualified qualified

[0279] *contrast

[0280] Examination of the refrigerated extracts revealed that formulations prepared using conventional GDO contained precipitate after thawing and / or the samples showed turbidity or opalescence. The precipitate appeared to be granular crystals distributed around the stopper and glass walls.

[0281] Figure 1 Shown are pre-filled syringes photographed under polarized light, pre-filled with sample No. 2 stored at 5°C for 14 months. These pictures were taken at 0 minutes, 5 minutes, 15 minutes and 30 minutes after removal from the climate chamber. Note that the white spots observed in the background are not present in the formulation, and the formulation appears completely transparent within 15 minutes of equilibration at RT.

[0282] Analysis of other samples (3-10) stored at 2°C-8°C showed the presence of precipitates which generally (but not always) re-dissolved within a few hours at room temperature, however in some samples, significant precipitates, turbidity and / or opalescence remained. Some samples stored at 5°C and 15°C showed opalescence when examined at room temperature for one hour. The opalescence was generally more pronounced in the control samples. Table 2 indicates "failures" when samples contained precipitates, or failed for other obvious reasons such as excessive turbidity, opalescence (which was not considered a complete failure). Thus, Example 1 illustrates the use of diacylglycerols having a fatty acid composition of at least 98% oleic acid (18:1) as determined according to Method C, 2.4.22 (determination of fatty acid composition by gas chromatography) of Ph. Eur. 9.0, to provide substantial improvement after storage under refrigerated conditions. Some samples were opalescent, thus motivating further exploration to provide consistent lipid-based formulations that can be used for low temperature storage (such as between 2°C-8°C).

[0283] HPLC analysis of extracts from samples No. 1 and 2 showed that the active agent was within specification for all samples and that refrigeration slowed the degradation of the active agent such that more than 90% of the original content was retained, indicating longer storage stability.

[0284] Example 2 - Exploration of Turbidity and Opalescence

[0285] Turbidity and / or opalescence appeared in some samples prepared in Example 1, although upon examination of preformulations identical to those in Example 1 stored under refrigerated conditions in glass vials, it was surprisingly noted that the preformulations did not show opalescence under visual inspection. In contrast to the syringes, the glass vials did not contain a pre-applied lubricant (silicone oil). Typically, glass syringes are treated with lubricants (such as silicone oil) to achieve acceptable injection forces, thereby allowing, for example, self-administration and ensuring compatibility with auto-injectors (e.g., considering injection time). Further studies were conducted to develop an acceptable lipid-based formulation suitable for storage under re-refrigerated conditions.

[0286] The following preformulation without active agent was prepared as described in Example 1 and approximately 0.2 mL was filled into a 1 mL glass syringe without pre-applied silicone oil. The syringe was sealed with a plunger, such as a suitable plunger sold by BD or West Corporation.

[0287] Table 3

[0288]

[0289]

[0290] *Regular pre-lubricated glass syringe (silicone oil)

[0291] 1 contrast

[0292] 2 A fatty acid composition containing at least 98% oleic acid (18:1)

[0293] 3 Citrate buffer containing 0.5 mg / mL EDTA sodium salt

[0294] 4 A substantially anhydrous system in which EDTA is dissolved in a lipid system using ethanolamine (ETA), for example, as described in WO 2018 / 060213 Visually assess samples as described in Example 1, for example, samples 11-14 stored at 2°C-8°C for 16 months and then visually inspected, and the results are presented in Table 4 and Figure 4 and Figure 5 middle.

[0295] Table 4:

[0296]

[0297] Samples 11 and 12 contained precipitate and were unacceptable. Sample 13 was deemed acceptable for application at first observation, while Sample 14 still exhibited opalescence throughout the evaluation.

[0298] Example 3 - Determining the force required for injection.

[0299] Typical injection devices deliver forces up to around 20-25 N. To determine the appropriate configuration of formulation, needle, volume, injection mechanism and injection time, studies can be performed using appropriate samples. Methods based on ISO 11040 are suitable. Needle characterization is performed according to ISO 9626:2016.

[0300] A pre-filled syringe containing 1 ml of a lipid controlled release formulation (placebo or containing an active agent) and not containing a silicone lubricant (non-siliconized) is placed in a material tester with a 100N load cell. The plunger stopper (lubricated) does not need to be moved when the plunger rod is installed to avoid affecting the "loose force" measurement. After removing the needle cover, the test is performed at a selected speed to provide the delivery of the correct dose within a specified period of time. The necessary load is measured over time until the plunger stopper contacts the shoulder of the syringe barrel, at which point the test is stopped. The maximum force in the stroke range of 0 mm to ≤5 mm in the force diagram is used to determine the loose force, and the sliding force is calculated based on the average force between the end of the loose period to just before the end of the plunger stroke, and the sliding force can be calculated alternatively using the maximum force from just after the end of the loose period to just before the end of the plunger stroke.

[0301] Testing of lipid controlled release formulations has shown that such formulations closely follow the established Hagen-Poiseuille theory, in which injection time is linearly related to viscosity, needle length, and fill volume; injection time depends on the fourth power of the internal syringe (barrel) diameter, and is inversely proportional to the residual force and the fourth power of the needle inner diameter.

[0302] Since the formulations fit the Hagen-Poiseuille theory well, the average force required for delivery (gliding force) for various viscosities, delivery times, and needle diameters can be calculated and a model developed. Examples based on the developed model are shown in the table below.

[0303]

[0304] Figure 2a (22G ultra-thin wall) and Figure 2b (23G thin wall) shows the variation of injection time with sliding force at various viscosities ranging from 100 to 1000 mPas.

[0305] The break-away force is defined as the maximum force required to move the plunger stopper within the syringe barrel within the range of 0 mm to ≤ 5 mm. The break-away force of the above pre-filled syringe containing 1 ml of the lipid controlled release formulation resulted in a good combination of the break-away force and the estimated sliding force, i.e., Figure 3 and are believed to be suitable for self-administration or for use in an auto-injector.

[0306] Comparative tests were performed with corresponding empty syringes without silicone lubricant. The test was stopped because a force of 45 N was insufficient to provide the required break-away and sliding forces sufficient for injection into air (i.e., the syringe plunger did not travel the required distance). No greater force was applied due to the risk of breaking the glass syringe. The break-away force can be analyzed according to ISO 11040-4:2015 (Glass syringes for injections).

[0307] A similar test was performed using a non-siliconized syringe with a barrel containing water, equipped with a 22G UTW needle and an unlubricated stopper. A force of 45 N was achieved without full injection of air.

[0308] The test was repeated using a non-siliconized syringe barrel filled with water, using a 22G UTW needle and a silicone lubricated stopper. The results show that injection into air using a non-siliconized syringe barrel but a siliconized stopper is possible, but requires a lot of force. Breakaway forces of around 13, 20 and 18 N were obtained (with plunger travel of 0.5, 1 and 5 mm / s), respectively, and these values ​​are considered high considering the low viscosity of water.

[0309] Filling a non-lubricated syringe with the lipid composition disclosed herein does meet the requirements of release force and sliding force. Therefore, it is found that the syringe (preferably lubricated) sealed with a plunger stopper and filled with a lipid composition as disclosed herein, which does not contain lubricating silicone oil, can be stored for an extended period at 2 ° C-8 ° C, and visible precipitate and / or turbidity, such as opalescence, will not occur after repair at room temperature. In addition, this pre-filled syringe does not require excessive injection force, so that the lipid composition of a dedicated amount (e.g., 0.1-3ml) is injected within an acceptable period of time (such as 3-25s, such as 5-20s, such as 5-15s). The example of the force required for the plunger injection preparation is 5-25N, such as 8-20n. The pre-filled syringe described herein does meet the overall goal of enabling the syringe containing the activating agent that needs this low temperature storage (e.g., 2 ° C-8 ° C) to be stored at low temperature, and injectability and product consistency (no precipitate and transparent liquid) are achieved by the aspects and embodiments described herein.

Claims

1. A glass syringe or glass barrel containing a lipid-based preformulation, wherein at least the inner surface of the glass syringe or glass barrel is in contact with the lipid-based preformulation and the inner surface does not contain a pre-applied silicone lubricant, at least the inner surface of the glass syringe or glass barrel does not contain a pre-applied lubricant, and wherein the lipid-based preformulation comprises a) 20-80 wt% of diacylglycerols whose fatty acid composition is at least 98% oleic acid (18:1) as determined according to Ph. Eur. 9.0, Method C, 2.4.22; b) 20-80 wt% of phospholipids; c) 1-30 wt % of a solvent; d) biologically active agents; wherein a) and b) account for at least 94 wt% of the total lipid content of the lipid-based preformulation, and the lipid-based preformulation is a clear liquid having a viscosity of less than 1000 mPas at 20°C and is substantially free of visible precipitate after storage at a temperature of less than or equal to 10°C for at least 1 month followed by equilibration at room temperature for a period of at least one hour, according to USP <790> Determined.

2. The glass syringe or glass barrel of claim 1, wherein the preformulation is substantially free of visible precipitate after storage at a temperature of 0-10°C for at least 1 month followed by equilibration at room temperature for a period of at least one hour, according to USP <790> Determined.

3. The glass syringe or glass barrel of claim 1, wherein the preformulation is substantially free of visible precipitate after storage at a temperature of 2-8°C for at least 1 month followed by equilibration at room temperature for a period of at least one hour, according to USP <790> Determined.

4. The glass syringe or glass barrel of claim 1, wherein the preformulation contains: no more than (NMT) 6000 particles greater than or equal to 10 μm and / or NMT 600 particles greater than or equal to 25 μm, as determined by USP <788> Determined.

5. The glass syringe or glass barrel according to any one of claims 1 to 4, wherein the diacylglycerols contain no more than 2 wt% of monoacylglycerols.

6. The glass syringe or glass barrel according to any one of claims 1 to 5, wherein the preformulation comprises no more than 5 wt% of triacylglycerols.

7. The glass syringe or glass barrel according to any one of claims 1-6, wherein the phospholipid is selected from the group consisting of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), dioleylphosphatidylcholine and mixtures thereof.

8. The glass syringe or glass barrel according to any one of claims 1 to 7, wherein the phospholipid is phosphatidylcholine (PC) or dioleylphosphatidylcholine.

9. The glass syringe or glass barrel according to any one of claims 1 to 8, wherein the ratio of diacylglycerols to phospholipids is in the range of 20:80 to 80:

20.

10. The glass syringe or glass barrel according to any one of claims 1 to 9, wherein a) and b) account for at least 95 wt% of the total lipid content of the preformulation.

11. The glass syringe or glass barrel according to any one of claims 1 to 10, wherein the solvent is selected from the group consisting of ethanol, propylene glycol (PG), water for injection (WFI), benzyl alcohol, dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP) and mixtures thereof.

12. The glass syringe or glass barrel according to any one of claims 1 to 11, wherein the solvent is ethanol or a mixture of ethanol and propylene glycol (PG).

13. The glass syringe or glass barrel according to any one of claims 1 to 12, wherein the biologically active agent is an agent that needs to be stored at a temperature below 10°C.

14. The glass syringe or glass barrel of any one of claims 1-13, wherein the biologically active agent is a peptide active agent.

15. The glass syringe or glass barrel of any one of claims 1-13, wherein the active agent is a cyclic and / or constrained peptide active agent.

16. The glass syringe or glass cartridge of any one of claims 1 to 15, which is stored for at least 1 month.

17. The glass syringe or glass barrel of any one of claims 1-16, which is free of visible precipitation and / or turbidity after a period of one hour of equilibration at room temperature.

18. A glass syringe or glass barrel according to any one of claims 1 to 17 containing 0.1 to 3 ml of the lipid-based preformulation.

19. The glass syringe or glass barrel according to any one of claims 1-18, wherein the plunger sealing the syringe or barrel has a breakaway force of no more than 35N.

20. The glass syringe or glass barrel according to any one of claims 1-18, wherein the plunger sealing the syringe or barrel has a sliding force of no more than 35N.

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