Lipid controlled release composition

Abstract

The present disclosure provides a glass syringe or barrel containing a lipid-based pre-formulation suitable for refrigerated storage.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of May 29, 2020, a Chinese patent application number of 202080036894.3, and an invention title of "Lipid Controlled Release Composition", and this application claims the priority of a Swedish application with an application number of 1950645-0. Technical Field

[0002] This disclosure relates to lipid compositions (especially those suitable for pharmaceutical formulations) and pre-formulations containing such lipid compositions. This disclosure further relates to the use of certain lipid compositions in preventing or reducing the formation of long-lived precipitates during the storage of lipid drugs. Background Art

[0003] Many bioactive agents (including pharmaceuticals, nutrients, vitamins, etc.) have a "function window". That is, within a certain 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.

[0004] Some bioactive agents have a long biological half-life and / or a wide function window, and thus can be administered occasionally, yet can maintain a functional biological concentration for a relatively long period (e.g., 6 hours to several days). In other cases, the clearance rate is high and / or the function window is narrow, so in order to maintain the biological concentration within this window, regular (or even continuous) small doses are required. This can be particularly difficult when a non-oral administration route (e.g., parenteral administration) is desired or required (because self-administration may be difficult), and thus leads to inconvenience and / or poor compliance. In such cases, a single administration that can provide a therapeutic level of the active agent throughout the entire period of need would be advantageous.

[0005] Some patients receiving treatment usually need to maintain a therapeutic dose for a relatively long period and / or continue treatment for several months or years. Therefore, a depot system that allows loading and controlled release of a larger dose over a longer period would provide a significant advantage over conventional delivery systems.

[0006] Certain formulations of the present disclosure give rise to non-lamellar liquid crystalline phases upon administration. The use of non-lamellar phase structures, such as liquid crystalline phases, in the delivery of bioactive agents is now relatively well established. An efficient lipid depot system is described in WO 2005 / 117830. However, there is still room for improvement in depot formulations that have improved performance in certain aspects.

[0007] In particular, it has been observed that when certain lipid-based compositions, such as the lipid depot system described in WO 2005 / 117830, are restored to room temperature after storage under refrigerated conditions, they may retain a turbid or "cloudy" appearance. Even when the pre-formulation is equilibrated at room temperature, this turbidity persists. Turbidity is undesirable in injectable drugs and may be prohibited for regulatory and / or safety reasons. As used herein, "turbidity" is used to indicate a lack of clarity in a solution. This may be due to the suspension, precipitation, separation, or other reasons of liquid or solid materials in the solution.

[0008] Turbidity (including the formation of opalescence and precipitates in the drug, which take a long time to redissolve or remain insoluble) may mean that the drug is more difficult to administer to a subject or in many cases such administration will be prohibited. Since some active agents must be stored under refrigerated conditions to prevent degradation of the active agent, the formation of these long-lasting 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.

[0009] Accordingly, 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 precipitates.

[0010] 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 (on a manufacturing scale) in combination with a specific glass syringe that has an inner surface in contact with the lipid-based formulation and is free of silicone oil or even pre-applied lubricants. By preparing a lipid-based formulation containing a high-purity diacylglycerol composition, such as diolein, and filling it in a glass syringe free of silicone oil, the formation of precipitates and opalescence / turbidity after storage under refrigerated conditions and subsequent equilibration at room temperature is unexpectedly reduced while maintaining injectability. SUMMARY OF THE INVENTION

[0011] 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 pre-applied silicone lubricant, and wherein the lipid-based preformulation comprises

[0012] a) 20 - 80 wt% of diacylglycerol, the fatty acid composition of which is at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0;

[0013] b) 20 - 80 wt% of phospholipids;

[0014] c) 1 - 30 wt% of a solvent;

[0015] d) a bioactive agent;

[0016] 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, as determined according to USP <790>.

[0017] In one aspect, the glass syringe or glass barrel contains a lipid-based preformulation, wherein the preformulation contains or consists of: not more than (NMT) 6000 particles greater than or equal to 10 μm (precipitate and / or turbidity) and / or NMT 600 particles greater than or equal to 25 μm (precipitate and / or turbidity), as determined by USP <788>.

[0018] 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 appended claims and the examples 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, before administration and is allowed to equilibrate at room temperature before administration.

[0019] From a third aspect, the present disclosure provides the use of a diacylglycerol composition in preventing or reducing the formation of precipitates that persist over time in a pre-formulation comprising the diacylglycerol composition and at least one biocompatible organic solvent, wherein the fatty acid composition of the diacylglycerol composition is at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0.

[0020] From a fourth aspect, the present disclosure provides a method for preventing or reducing the formation of precipitates that persist over time in a pre-formulation when the pre-formulation 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 pre-formulation comprising:

[0021] (i) a diacylglycerol composition; and

[0022] (ii) at least one biocompatible organic solvent;

[0023] The method comprises forming the pre-formulation with a diacylglycerol composition according to the first aspect. An example of the fourth aspect is a method for preventing or reducing the formation of precipitates that persist over time in a lipid-based pre-formulation when the lipid-based pre-formulation 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 pre-formulation comprising:

[0024] a) (i) 20 - 80 wt% of diacylglycerol, the fatty acid composition of which is at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0;

[0025] b) 20 - 80 wt% of phospholipids;

[0026] c) 1 - 30 wt% of a solvent;

[0027] d) a bioactive agent.

[0028] From a fifth aspect, the present disclosure provides a pre-filled glass syringe or glass barrel according to the first aspect, pre-filled with a lipid-based composition and comprising a barrel having an inner surface, wherein the portion of the inner surface of the barrel that is in constant 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), where substantially free of any pre-applied lubricant is understood to mean that no lubricant is added during or after the manufacture of the syringe, i.e., the inner surface is substantially free of lubricant, such as silicone oil, before filling the syringe with the lipid-based composition disclosed herein. Examples of suitable syringes are commercially available, such as those sold by the Gerresheimer Group, Schott AG, and Becton, Dickinson and Company, e.g., 1 mL glass syringes, provided that the inner surface is free of silicone oil or lubricant.

[0029] In another aspect, the present disclosure provides a method of administering a pre-formulation according to the present disclosure contained in a silicone oil-free syringe to a patient in need thereof, wherein the syringe containing the pre-formulation is maintained at a refrigerated temperature (e.g., between 2 °C and 8 °C) until about 1 h before administration (e.g., up to 24 months before administration), and allowed to equilibrate at room temperature (15 °C - 25 °C, e.g., at 25 °C) for about 1 hour before administration.

[0030] The pre-formulation should be a clear liquid, e.g., having no visible turbidity at the time of administration. Turbidity can be detected by visual inspection in accordance with USP <790>.

[0031] In another aspect, the present disclosure provides a syringe according to the first aspect, wherein the pre-formulation has a stability of at least six months, such as at least 12 months, such as at least 18 months, when stored at 2 °C - 8 °C.

[0032] In another aspect, the present 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 that are suitable for the syringes described herein (such as 1 mL glass syringes).

[0033] Additional aspects and embodiments are provided in the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 : Photographs of a pre-filled syringe according to the present disclosure taken at 5 °C after 14 months of storage, taken at 0 minutes, 5 minutes, 15 minutes, and 30 minutes after removal from the climatic chamber, in polarized light.

[0035] Figure 2aand Figure 2b show the injection time and sliding force graphs of formulations of different viscosities injected through 22G TW and 23G UTW needles, respectively.

[0036] Figure 3 shows the correlation between the estimated sliding force and the pull-off force.

[0037] Figure 4 and Figure 5 : Photograph of a prefilled glass syringe according to Example 2. DETAILED DESCRIPTION

[0038] The present disclosure provides a high-purity diacylglycerol composition. As used herein, the term "high-purity diacylglycerol composition" should be understood to mean a composition or formulation comprising at least 97.0 wt% of diacylglycerol, the diacylglycerol having two fatty acid residues, each having 16-20 carbon atoms and one or two carbon-carbon double bonds, for example, the fatty acid composition being at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the fatty acid composition by gas chromatography) of the European Pharmacopoeia 9.0.

[0039] Unless otherwise indicated, all % are specified herein throughout by weight. Weight percentages (%) may be abbreviated, for example, as wt%. Further, unless otherwise indicated, the indicated weight % is of the total composition or formulation including all components indicated herein. Unless otherwise indicated, when a weight percentage is given in relation to a salt of an active agent compound, the weight percentage relates to the amount (or equivalent) of the free base. In certain instances, the wt% of the specified salt is provided (but indicated where appropriate), and can be readily converted to the corresponding weight of the free base.

[0040] When a composition or formulation is represented herein as "consisting essentially of certain components", the specified components provide the basic properties of the formulation, such as when the specified components constitute at least 95%, preferably at least 98% of the formulation. This applies equally to any component or ingredient that may be formed from more than one material. Similarly, any use herein of "about", "around", "approximately" or similar language indicates that the specified amount is the primary embodiment, but the actual amount should not vary significantly from the specified amount, as judged by one of ordinary skill in the art. Unless the context prohibits, this will generally be ±10%, ±5% or ±1% of the specified value.

[0041] In this text, particularly with reference to the claims, in cases where the language "comprises" a pharmaceutical agent or "consists of" a pharmaceutical agent or a component "selected from the group consisting of", this language is used to indicate two embodiments; the open group of the "comprises" embodiment and the closed group of the "consists of" embodiment. In the latter case, the list of pharmaceutical agents and components is considered closed and can be considered to end with the last instance of the list "and". Thus, this language can be interpreted as "selected from the group consisting of... and...".

[0042] Whenever the terms "comprises" or "contains" are used in the aspects, embodiments, claims, etc. of this disclosure, such terms shall be understood to encompass aspects, embodiments, and claims in which the said terms have been replaced with "consisting essentially of" or "consisting of". A specific example is whenever the term "a glass syringe or glass barrel containing a lipid-based pre-formulation" appears, the following are also considered to be explicitly contemplated: "a glass syringe or glass barrel consisting essentially of a lipid-based pre-formulation" and "a glass syringe or glass barrel consisting of a lipid-based pre-formulation".

[0043] 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 for all embodiments are described herein. Salts such as halides (especially chlorides), acetates, pamoates, etc. are examples of suitable salts of the basic moiety. Salts of alkali metals, alkaline earth metals, amines, or alkylamines are examples of suitable salts of the acidic moiety.

[0044] The term "pre-formulation" or pre-formulation is used herein to denote a pharmaceutical formulation capable of being injected to produce a controlled-release "depot" formulation in a subject. The pre-formulation may optionally consist essentially only of the components indicated herein (including other optional components indicated hereinbelow and in the appended claims where appropriate), and in one aspect consists entirely of such components.

[0045] In one embodiment, a diacylglycerol composition in any suitable aspect comprises at least 97.5 wt%, such as at least 98.0 wt%, such as at least 98.5 wt% diacylglycerol, the diacylglycerol 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 having a fatty acid composition of at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0.

[0046] Although diacylglycerol compositions are known in the prior art, diacylglycerol compositions having the same high purity as the diacylglycerol compositions disclosed herein have not previously been used for manufacturing pharmaceutical products (e.g., lipid-based pre-formulations 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).

[0047] Surprisingly, the inventors have determined that when using the high-purity diacylglycerol compositions disclosed herein rather than the conventional (lower purity) diacylglycerol compositions known in the prior art to produce lipid-based formulations, the turbidity observed after thawing the lipid-based composition that has been stored under refrigerated conditions is reduced or eliminated (e.g., determined by visual inspection according to USP <790>). The inventors have also determined a method for synthesizing high-purity diacylglycerol.

[0048] Without wishing to be bound by theory, it is believed that the presence of saturated impurities in the lipid-based composition causes the turbidity observed when the formulation incorporating the composition is stored under refrigerated conditions and then equilibrated at room temperature. By preparing the formulation with a high-purity diacylglycerol composition, the amount of saturated impurities in the formulation can be reduced, and thus the amount of insoluble long-lived precipitates formed after refrigerated storage and subsequent thawing is also reduced.

[0049] 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%, of 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 the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0.

[0050] The fatty acid residues of the desired diacylglycerol each independently have 16 - 20 carbon atoms. In one embodiment, the fatty acid residues of the diacylglycerol 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.

[0051] The fatty acid residues of the desired diacylglycerol each independently have one or two carbon-carbon double bonds. In one embodiment, the fatty acid residues of the diacylglycerol 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.

[0052] In one embodiment, the fatty acid residues of the diacylglycerol are independently oleic acid residues (C18:1) or linoleic acid residues (C18:2). The name "CX:Z" represents a hydrocarbon chain having X carbon atoms and Z degrees of unsaturation (especially double bonds). In one embodiment, the fatty acid residues are each oleate residues or each are linoleate residues. In one embodiment, the fatty acid residues are each oleate residues, i.e., the diacylglycerol is diolein. In all aspects herein, a key embodiment is that the diacylglycerol referred to herein can be diolein, dilinolein, or a mixture thereof. In one embodiment, in all aspects the diacylglycerol referred to herein can be diolein.

[0053] 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).

[0054] In one embodiment, the diacylglycerol composition contains 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 contains no more than 2.5 wt%, such as no more than 2 wt%, such as no more than 1.5 wt% of triacylglycerol.

[0055] Pre - formulation

[0056] In one aspect, the present disclosure relates to a precursor formulation (also referred to as a "pre - formulation") that comprises: i) a diacylglycerol composition having a fatty acid composition of at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0; and ii) at least one biocompatible organic solvent. The diacylglycerol composition of component i) can be the diacylglycerol composition described herein.

[0057] As used herein, the term "formulation" or "pre - formulation" refers to a mixture of components (i) and (ii) and optionally other components. The pre - formulation typically has a low viscosity. The term "pre - formulation" means that the pre - formulation forms or is capable of forming at least one non - lamellar (especially liquid crystalline) phase structure upon contact with an excess of aqueous fluid.

[0058] The term "depot" refers to a composition formed after the pre - formulation 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 the exchange of solvent (ii) for the aqueous fluid and / or by the addition of aqueous fluid to the lipid structure. Depots generally have a much higher viscosity than the corresponding pre - formulations and provide a gradual release of any active agent contained within the depot.

[0059] In one embodiment, the pre - formulations of the present disclosure produce a non - lamellar phase (e.g., a non - lamellar liquid crystalline phase) after administration. The use of non - lamellar phase structures such as liquid crystalline phases in the delivery of bioactive agents is now relatively well - established. An effective lipid depot system is described in WO 2005 / 117830 (incorporated herein by reference). For a description of the most favorable phase structures for such formulations, note the discussion in WO 2005 / 117830, particularly on page 29 thereof. Preferably, the pre - formulations according to the present disclosure have a molecular solution or L2 phase structure before administration.

[0060] The pre - formulations of the present disclosure form or are capable of forming at least one liquid crystalline phase structure upon contact with an excess of aqueous fluid. Herein, "excess aqueous fluid" should be understood to mean that the volume of the aqueous fluid is at least 10 times (such as 10 to 1000 times) larger than the volume of the pre - formulation.

[0061] In one embodiment, applicable to all aspects of the present disclosure, the pre - formulations according to the present disclosure have a molecular solution or L2 phase structure (before administration). The pre - formulation forms a non - lamellar (e.g., liquid crystalline) phase after administration. This phase change is generally caused by the absorption of aqueous fluid from the physiological environment, as indicated herein. Although it has been previously determined in WO 2012 / 160213 that strict control amounts of water can be tolerated as long as a monohydric alcohol solvent is present, it should be understood that the pre - formulation is exposed to a large amount of aqueous fluid in vivo after administration, which results in the formation of a non - lamellar phase. Generally, the pre - formulation will form a non - lamellar phase after contact with at least an equal - volume amount of aqueous fluid.

[0062] The viscosity of the pre - formulations of the present disclosure will be controlled by their formulation, but will generally be within a range that can be effectively delivered by syringe or auto - injector within a tolerable period (e.g., less than 30 seconds). Suitable viscosities can 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.

[0063] Component (i): Diacylglycerol composition

[0064] The pre - formulated product of the present disclosure comprises a diacylglycerol composition, the fatty acid composition of which is at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0. In one embodiment, the diacylglycerol composition is the only diacylglycerol present in the pre - formulated product, i.e., the pre - formulated product is substantially free of any diacylglycerol other than the diacylglycerol composition, the fatty acid composition of which is at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0.

[0065] The main difference between the pre - formulated product of the present disclosure and those known in the prior art is that the pre - formulated product of the present disclosure comprises a high - purity diacylglycerol composition as defined herein. Unexpectedly, the inventors have determined that when using the high - purity diacylglycerol composition of the present disclosure (optionally in combination with a syringe having an inner surface free of pre - applied lubricant) to prepare a pre - formulated product, the formation of long - term 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 one month or longer).

[0066] Without being bound by theory, it is believed that after storage under refrigerated conditions, the formation of long - term precipitates in prior - art formulations is due to the presence of saturated impurities in the lipid component. Using the high - purity diacylglycerol composition of the present disclosure reduces the level of saturated impurities in the formulation and thus prevents or reduces the formation of said long - term precipitates.

[0067] Component (ii): Biocompatible organic solvent

[0068] Component (ii) of the pre - formulated product 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. Since the pre - formulated product produces or is capable of producing a depot composition after contact with an excess of aqueous fluid after administration (e.g., in vivo), it is desirable that these solvents are tolerated by the subject and are capable of mixing with the aqueous fluid and / or diffusing or dissolving from the pre - formulated product into the aqueous fluid. Thus, solvents with at least moderate water solubility are preferred. As will be described below, component (ii) can include polar co - solvents such as propylene glycol.

[0069] As used herein, the term "biocompatible organic solvent" shall be understood to mean a solvent that can be safely used in mammalian subjects (e.g., humans). Generally, a biocompatible organic solvent will have an LD50 (calculated by oral administration in rats) of 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 readily obtained from MSDS sheets.

[0070] In embodiments, 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) can comprise or consist of a monohydric alcohol solvent (preferably ethanol) and a polar co-solvent. A mixture comprising ethanol and propylene glycol or consisting of the same is suitable. In embodiments, the biocompatible organic solvent is a biocompatible oxygenated organic solvent.

[0071] 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.

[0072] Component (ii) can comprise two or more components from the above solvent list, particularly a monohydric alcohol solvent and a solvent selected from amides, sulfoxides, or dihydric alcohol solvents. Any solvent that is not a monohydric alcohol solvent can be referred to herein as a co-solvent. When two or more solvents are present, suitable combinations include ethanol and an amide (such as ethanol and N-methylpyrrolidone (NMP)), ethanol and a sulfoxide (such as ethanol and dimethyl sulfoxide (DMSO)), or ethanol and a dihydric alcohol solvent or polyhydric alcohol solvent (such as ethanol and propylene glycol (PG)). Ethanol and PG form one embodiment.

[0073] Suitable combinations of solvents are ethanol and PG, especially when the ratio of ethanol to PG is from 1:5 to 20:1, such as from 1:1 to 10:1, such as from 1.5:1 to 8:1, such as from 2:1 to 5:1 (e.g., around 3:1, such as from 2.8:1 to 3.2:1). In one embodiment, component (ii) can 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) can comprise or consist of ethanol, or can comprise or consist essentially of a mixture of ethanol and PG. In one embodiment, component (ii) comprises or consists essentially of propylene glycol.

[0074] The amount of component (ii) in the pre - formulation will have a significant impact on several characteristics. In particular, the viscosity and the release rate (and duration) will vary significantly with the solvent level. Thus, the amount of solvent will be at least sufficient to provide a low - viscosity mixture, but the amount of solvent will be additionally determined to provide the desired release rate. This can be determined by conventional methods according to the following examples. Typically, a level of 1% to 30% (especially 2% to 25%) of solvent will provide suitable release and viscosity characteristics. This will preferably be 2% to 20%, preferably 5% to 15%, and an amount around 10% (e.g., 10% ± 3%) is efficient. These levels include any co - solvents present as part of component (ii), as mentioned above.

[0075] As pointed out above, the amount of component (ii) in the pre - formulations 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.

[0076] The phase behavior of any pre - formulation, 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 cryo - transmission electron microscopy (cryo - TEM) to observe solutions, L2 or L3 phases, or liquid - crystalline phases or, in the case of cryoTEM, dispersed segments of such phases. Viscosity can be measured directly by standard means. As described herein, a suitable practical viscosity is one that can be effectively injected and especially sterile - filtered. This can be readily evaluated as indicated herein.

[0077] Preferably, component (ii) contains little or no halogen - substituted hydrocarbons, as these tend to have lower biocompatibility.

[0078] As used herein, component (ii) can be a single solvent or a mixture of suitable solvents, but generally has a low viscosity. This is important because one of the key aspects of the present disclosure is that it provides a pre-formulation having a low viscosity, and the main role of the suitable solvent is to reduce this viscosity. This reduction will be attributed to a combination of the effect of the lower solvent viscosity and the effect of the molecular interactions between the solvent and the lipid composition. One observation of the present inventors is that the oxygenated solvents having a low viscosity described herein have very favorable and unexpected molecular interactions with the lipid moiety of the composition, thus providing a non-linear reduction in viscosity upon addition of a small volume of solvent.

[0079] The viscosity of the "low viscosity" solvent component (ii) (single solvent or mixture) should generally not exceed 18 mPas at 20 °C. This 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.

[0080] In WO 2012 / 160213 it is described that adding a polar solvent in addition to a monohydric alcohol solvent results in a number of 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 monohydric alcohol 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 apply equally to mixtures of monohydric alcohol solvents and polar co-solvents.

[0081] Typical co-solvents will have a relatively high dielectric constant corresponding to their high polarity. Thus, suitable co-solvents 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 suitable for use in combination with some active agents.

[0082] In a particularly preferred embodiment, component (ii) comprises, consists essentially of, or consists of a mixture of a monohydric alcohol solvent and a polar co-solvent. In one embodiment, the polar co-solvent can be a C3-C6 organic solvent that is a diol, i.e., a C3-C6 organic solvent containing two hydroxyl groups. The diol solvent is preferably propylene glycol. When present, the polar co-solvent is included at a level of 2 to 12 wt.%, such as 3 to 10 wt.%, especially 4 to 9 wt.%, of the pre-formulation. 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).

[0083] When both an organic monohydric alcohol solvent and a polar co-solvent are present, such as ethanol and PG, the ratio of the monohydric alcohol solvent to the polar co-solvent 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 monohydric alcohol and diol components are very suitable.

[0084] In a particularly preferred embodiment, 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 of ethanol to PG (w / w) 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 (ratio 40:60 to 60:40 (w / w)).

[0085] 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 embodiments herein (e.g., 0.1 to 1.0 wt%).

[0086] In some embodiments, particularly suitable combinations of solvents for component (ii) include a monohydric alcohol solvent and a co-solvent selected from the group consisting of amides, sulfoxides, or diols. Particularly preferred combinations are ethanol and an amide, ethanol and a sulfoxide, or ethanol and a diol. Particularly preferred combinations are ethanol and propylene glycol (PG); ethanol and dimethyl sulfoxide (DMSO); and ethanol and N-methyl-pyrrolidone (NMP).

[0087] When present, a suitable amount of the co-solvent will generally be greater than 1% by weight of the pre-formulation, such as 2% - 15%, particularly 4% - 12%, especially 4 - 10 wt.%. The combination of a monohydric alcohol solvent and a co-solvent as component (ii) has potential advantages in the compositions of the present disclosure. In particular, by including some co-solvents that are miscible with the monohydric alcohol component, the slight sensation that may be caused by the alcohol content at the injection site can be substantially eliminated. Thus, in one embodiment, the ratio of the monohydric alcohol component to the co-solvent 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 the components (w / w) are very suitable.

[0088] Optional phospholipid component

[0089] In one embodiment, the pre-formulation of the present disclosure comprises a phospholipid component.

[0090] In embodiments, the phospholipid component is present in an amount of 15 to 50 wt.% of the pre-formulation. In some embodiments, the amount of phospholipid can be 15 to 45 wt.%, such as 20 to 45 wt.%.

[0091] In embodiments, the ratio of the diacylglycerol composition to the 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.

[0092] Phospholipids contain a polar head group and at least one non-polar tail group. In one embodiment, the phospholipid (e.g., phosphatidylcholine (PC)) will contain two non-polar groups. In particular, C12 to C20 (such as C16 to C18) acyl groups having zero, one or two unsaturations (e.g., 1 or 2 unsaturations) in either case are very suitable as part of the non-polar groups forming the phospholipid. In embodiments, at least 50% of the non-polar groups are oleoyl groups (C18:1).

[0093] In one embodiment, at least 50% (such as at least 75% or at least 90%) of the non-polar groups of the phospholipid are C16 to C18 (e.g., C18:1) moieties. In one embodiment, approximately 100% of the non-polar groups of the phospholipid are such moieties.

[0094] In another embodiment, at least 50% (such as at least 75% or at least 90%) of the non-polar groups of the phospholipid are C18 (e.g., C18:1) moieties. In one embodiment, approximately 100% of the non-polar groups of the phospholipid are such moieties.

[0095] In an embodiment, the phospholipid comprises or consists of a phospholipid that does not form a non-lamellar liquid crystalline phase structure as a pure compound in water at 25 °C. In an embodiment, the phospholipid comprises or consists 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.

[0096] The phospholipid moiety can be derived from natural sources. Suitable sources of phospholipids include eggs, heart (e.g., bovine), brain, liver (e.g., bovine), and plant sources, including soybeans. Such sources can provide one or more components of the phospholipid fraction, which can comprise any mixture of phospholipids.

[0097] Suitable polar head groups of the phospholipid include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. In one embodiment, the pre-formulation 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 using at least 50% by weight of PE based on the total amount of phospholipids can result in improved depot robustness.

[0098] In an embodiment, the phospholipid comprises or consists of one or more PCs. For example, at least 50% of the head groups of the phospholipid should be PC, such as more than 65% of the head groups, especially more than 85% or more than 90%. PC from a single source (e.g., soy PC) or a mixture of PCs from different sources (e.g., soy PC and egg PC) can be used. In an embodiment, the PC fraction contains at least 50% soy PC, such as at least 75% soy PC or substantially pure soy PC. In an embodiment, the PC fraction contains at least 50% egg PC, such as at least 75% egg PC or substantially pure egg PC.

[0099] In an 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 can be obtained from various suppliers, including Lipoid. Naturally derived PC typically contains 18:2 fatty acid as the major fatty acid component and 16:0 and / or 18:1 as minor fatty acid components. In an embodiment, the ratio between (18:2 fatty acid: other fatty acids) is from 1.5:1 to 6:1. PC having approximately 60%-65% 18:2, 10% to 20% 16:0, and 5%-15% 18:1 and the remainder mainly other 16-carbon and 18-carbon fatty acids is particularly suitable and is typical soy PC.

[0100] In alternative but equally suitable embodiments that are 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 suitable for compositions that require stability upon 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.

[0101] In one embodiment, the pre-formulation of the present disclosure consists at least in part of synthetic DOPC (i.e., a PC having at least 95% PC head groups and at least 90% oleoyl (C18:1) acyl groups) and has storage stability at 15°C - 25°C, which is defined as less than 5% degradation of the active agent (as determined by HPLC) after at least 6 months, such as at least 12 months or at least 24 months.

[0102] Since the pre-formulation 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 that are naturally present in mammals.

[0103] Synthetic or highly purified PCs (such as dioleoyl phosphatidylcholine (DOPC) and palmitoyl oleoyl phosphatidylcholine (POPC)) and various other highly purified PCs described herein are well suited as all or part of the phospholipids. As used herein, the term "highly purified" refers to a PC derived from a natural source that has 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 each of the two acyl chains within the PC independently has 16 to 20 carbons, at least one acyl chain has at least one degree of unsaturation in the carbon chain and no more than four degrees of unsaturation in the two carbon chains.

[0104] Generally, this may be a phospholipid wherein at least 95% of the phospholipids have PC head groups and at least 95% C16 to C20 acyl chains (which have 0 to 3 degrees of unsaturation).

[0105] In an embodiment, the synthetic PC is DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine). In other embodiments, the synthetic PC can comprise or consist of the following: 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-2-palmitoyl-sn-glycero 3-phosphocholine); MSPC (1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine); PMPC (1-palmitoyl-2-myristoyl-sn-glycero-3-phosphocholine); POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine); PSPC (1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine); SMPC (1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine); SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine); and SPPC (1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine), or any combination thereof. In all cases, the synthetic PC will preferably contain no more than 5% (e.g., 0.01% to 5%) of other materials, such as no more than 2% or no more than 1% of other materials.

[0106] Active agent

[0107] The pre-formulations of the present disclosure contain active agents, also known as bioactive agents. The pre-formulations of the present disclosure optionally contain one or more peptide or non-peptide active agents. It is important to note that the present disclosure is generally applicable, and thus it is contemplated that the present disclosure is applicable to pre-formulations containing any bioactive agent of interest (especially those that require refrigerated storage) or even pre-formulations that are completely free of bioactive agents. A bioactive agent can be any compound having a desired biological or physiological effect, such as a peptide, protein, drug, antigen, nutrient, cosmetic, fragrance, flavoring, diagnostic agent, pharmaceutical, 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 pharmaceutical agents (including drugs, vaccines, and diagnostic agents). A class of active agents suitable for 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 salts thereof. 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.

[0108] 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. As used herein, an active agent "requires refrigeration" if the active agent in the relevant formulation will degrade such that if the active agent (if appropriate, in the 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). 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.

[0109] In one embodiment, the active agent is an active agent that degrades to less than 90 wt% of its original level when stored at room temperature (e.g., 25 °C) for a period of 12 months.

[0110] 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), anti-cancer and / or anti-viral drugs (such as nucleoside analogs, paclitaxel, and their derivatives), anti-inflammatory drugs / agents (such as non-steroidal anti-inflammatory drugs and corticosteroids), cardiovascular drugs (including cholesterol-lowering and blood pressure-lowering agents), analgesics, anti-emetics (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.

[0111] Particularly suitable active agents include those that typically have a short residence time in the body due to rapid decomposition or excretion and those with poor oral bioavailability, alternatively where a long duration of action would be beneficial. These include peptide-, protein- and nucleic acid-based active agents, hormones and other naturally occurring agents in their native or modified forms. By administering such agents in the form of a depot composition (formed from the compositions disclosed herein), these agents are provided at a sustained level for a length of time that can be extended to days, weeks or even months, despite having a rapid clearance rate. This provides a significant advantage over multiple daily administrations over the same period in terms of stability and patient compliance. In one embodiment, the active agent thus has a biological half-life (after entry into 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 less. Suitable agents are also those with poor oral bioavailability (relative to the bioavailability obtained by injection), where 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 would benefit from cold storage (e.g., refrigeration). Cold storage improves the shelf life of the pre-formulation containing the active agent. The pre-formulations of the present invention may thus contain "refrigeration required" active agents (e.g., as described herein), may benefit from an extended shelf life (e.g., greater than 18 months (e.g., 24 months to 5 years) or a shelf life greater than 2 years), 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 pre-formulation during that storage period.

[0112] Where technically feasible, the active agents disclosed herein are also capable of being used in the form of their salts. When the "salt" of an active agent is referred to herein, this denotes a pharmaceutically acceptable salt. Such salts are well known in the art and include, for example, chlorides, acetates or pamoates of bases or alkali metal, alkaline earth metal, amino or alkylamino salts of acids.

[0113] The amount of bioactive agent to be formulated with the compositions disclosed herein will depend on the functional dose and the length of time the depot composition formed after administration provides sustained release. Generally, the dose formulated for a particular agent will be approximately equal to the normal daily dose multiplied by the number of days the depot provides release. Clearly, this amount will need to be adjusted for any side effects of the large dose at the start of treatment and so this is typically the maximum dose used. In any case, the precise amount suitable will be readily determined by appropriate experimentation.

[0114] In an embodiment, the compositions of the present disclosure may comprise one or more peptide active agents. The peptide active agent may comprise from 5 to 90 or 5 to 60 natural and / or synthetic amino acids (each independently a D- or L-isomer), particularly from 5 to 50 or 5 to 40 amino acids. In one embodiment, the active agent is a peptide active agent having no more than 45, such as no more than 30, amino acid residues. In embodiments, the peptide active agent is a cyclic and / or constrained peptide active agent. The ring size of the cyclic peptide active agent can be from 5 to 80 amino acids, for example, 6 to 80 or 8 to 45 or 10 to 35 amino acids.

[0115] Peptide- and protein-based active agents include the following human and veterinary drugs, selected from the group consisting of: adrenocorticotropic hormone (ACTH) and its fragments, angiotensin and its related peptides, antibodies and their fragments, antigens and their fragments, atrial natriuretic peptide, bioadhesive peptides, bradykinin and its related peptides, calcitonin peptides (including calcitonin and amylin and their related peptides), vasoactive intestinal peptide (VIP) (including growth hormone-releasing hormone (GHRH), glucagon, and secretin), opioid peptides (including proopiomelanocortin (POMC) peptides, enkephalin pentapeptides, dynorphin precursor peptides, and related peptides), pancreatic polypeptide-related peptides (such as neuropeptide (NPY), peptide YY (PYY), pancreatic polypeptide (PPY)), cell surface receptor protein fragments, chemotactic peptides, cyclosporine, cytokines, dynorphin and its related peptides, endorphins, and P-lidotropin fragments, enkephalin and its related proteins, enzyme inhibitors, immunostimulatory peptides, and polyamino acids, fibronectin fragments and their related peptides, gastrointestinal peptides, gonadotropin-releasing hormone (GnRH) agonists and antagonists, glucagon-like peptide 1 and 2, ghrelin, immunostimulatory peptides, insulin, and insulin-like growth factors, interleukins, luteinizing hormone-releasing hormone (LHRH) and its related peptides (equivalent to the GnRH agonists 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 anticancer peptides) (including angiostatin, antihypertensive peptides, antithrombotic peptides, and antimicrobial peptides); selected from the group consisting of proteins, such as immunoglobulins, angiopoietins, bone morphogenetic proteins, chemokines, colony-stimulating factors (CSF), cytokines, growth factors, interferons (type I and II), interleukins, leptin, leukemia inhibitory factor, stem cell factor, transforming growth factor, and tumor necrosis factor.One interesting class of bioactive agents applicable to 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); the posterior pituitary hormones, including vasopressin and oxytocin; the growth hormone family, including growth hormone (GH), human chorionic somatomammotropin (hCS), prolactin (PRL); the pancreatic polypeptide family, including PP, PYY, and NPY; melanin-concentrating hormone (MCH); orexin; gastrointestinal hormones and peptides, including GLP-1 and GIP; 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 a receptor affinity profile similar to the above peptides are also well-suited for the present disclosure.

[0116] Another significant advantage of the depot compositions of the present disclosure is the gradual release of the active agent over a long period without the need for repeated dosing. Thus, these compositions are very suitable for situations where patient compliance is difficult or unreliable, or where the dose level is very important, such as mood-altering active substances, those with a narrow therapeutic window, and those administered to children or to individuals with a lifestyle incompatible with a reliable dosing regimen, as well as "lifestyle" active substances where the inconvenience of repeated dosing may outweigh the benefits of the active substance. Specific classes of active substances that provide a particular advantage in this regard include contraceptives; hormones, including contraceptive hormones, and especially hormones 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 anti-convulsants.

[0117] 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 with an isoelectric point higher than pH 7, such as higher than pH 8.

[0118] In one aspect, polar active agents are included in the composition. Particularly suitable polar active agents include peptide and protein active agents, oligonucleotides, and small water-soluble active agents, including those listed above. Of particular interest in this regard are the peptide octreotide and other somatostatin-related peptides, interferons α and β, 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.

[0119] GnRH analogs form a particular class of active agents that may be included in the pre-formulations of the present disclosure. GnRH analogs include synthetic or semi-synthetic compounds that interact with the gonadotropin-releasing hormone receptor to elicit 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 portion from line 33 on page 1 to line 29 on page 2 of WO 2006 / 075125.

[0120] Since GnRH is a peptide hormone, typical GnRH analogs will be peptides, particularly peptides having 12 or fewer amino acids. Generally, 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 peptide may contain only amino acids selected from the 20 α-amino acids specified in the genetic code, or alternatively may contain their isomers, as well as 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 having 6 to 12 α-amino acids.

[0121] 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 pre-formulation comprises goserelin, consists essentially of it, or consists of it.

[0122] When present, GnRH analogs will generally be formulated at 0.02% to 12% by weight of the total composition (based on the amount of free base). Typical values will be 0.1% to 10%, such as 0.2% to 8%, such as 0.5% to 6%, for example 1% to 5%.

[0123] The dose of GnRH analog suitable for inclusion in the composition and thus the volume of the composition used will depend on the release rate (e.g., controlled by solvent type and amount) and release duration as well as the desired treatment level, the activity of the particular agent, and the clearance rate of the particular active substance selected. Generally, an amount of 0.1 to 500 mg per dose is suitable to provide a treatment level for 7 days to 180 days. In an embodiment, the dose of GnRH analog in the composition can be 1 to 200 mg. For compositions containing leuprorelin or goserelin, this level is typically around 1 to 120 mg (e.g., for 30 days to 180 days). For a depot designed to release over 30 days to 1 year, for example, for a depot designed to release over 3 to 6 months, the appropriate amount of leuprorelin between injections will be around 0.02 to 1 mg per day. Clearly, the stability of the active substance and the linearity of the release rate will mean that the loading and duration may not be a linear relationship. A depot administered every 30 days may have, for example, 2 to 30 mg of GnRH analog. A 90-day depot may have 6 to 90 mg of GnRH analog, such as one of the GnRH analogs indicated herein.

[0124] Somatostatin and somatostatin analogs form another class of particular active agents that can be included in the compositions of the present disclosure. Somatostatin (somatotropin release-inhibiting factor, 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 bioactive products are known in higher species, SST-14 and SST-28, the latter being a homolog of SST-14 with an N-terminal extension. SST-14 is a 14-residue cyclic peptide hormone with a disulfide bridge to create a type II β-turn at the critical binding sequence.

[0125] Suitable somatostatins for use in the present disclosure include endogenous SST-14 and SST-18, as well as somatostatin analogs, such as those disclosed in WO 2008 / 152401. Since SST-14 is a peptide hormone, generally, somatostatin receptor agonists will be peptides, especially peptides having 14 or fewer amino acids. Typically, such peptides will be structurally constrained, such as by being cyclic and / or having at least one intramolecular crosslink. Amide, ester, or especially disulfide crosslinks are very suitable. In some embodiments, the somatostatin analog will exhibit a type 2 β-turn. This turn is present in a key region of somatostatin. The peptide may contain only amino acids selected from the 20 α-amino acids specified in the genetic code, or may contain their isomers, as well as other natural and unnatural amino acids (generally α, β, or γ, L- or D-amino acids) and their analogs and derivatives.

[0126] Particularly suitable somatostatin analogs for use in the compositions of the present disclosure include those disclosed in the portion from line 24 on page 20 to line 19 on page 21 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 their salts. In some, the somatostatin or somatostatin analog is SST-14 or octreotide and their salts.

[0127] When present, the somatostatin receptor agonist will generally be formulated to be from 0.1% to 12% by weight of the total composition (based on the amount of free base). Typical values will be from 0.1% to 10%, such as from 0.5% to 9%, such as from 1% to 8%, for example from 1% to 7% or from 2% to 6%.

[0128] The dose of the somatostatin receptor agonist suitable for inclusion in the composition and thus the volume of the composition used will depend on the release rate (e.g., controlled by the type and amount of solvent), the duration of release, the desired therapeutic level, the activity of the particular active substance selected, and the clearance rate. Generally, an amount of somatostatin analog from 1 to 500 mg or 5 to 300 mg per dose is suitable to provide a therapeutic level for 7 days to 90 days. For octreotide, this level is generally around 10 to 180 mg (e.g., for 30 days to 90 days). Typically, between injections, the amount of octreotide is around 0.2 to 3 mg per day. Thus, a depot administered every 30 days will have 6 to 90 mg of octreotide, or a 90-day depot will have 18 to 270 mg of octreotide.

[0129] For pasireotide, the dose will generally be an amount of about 0.05 to 40 mg for a depot duration of one week, such as 0.1 to 20 mg for a weekly duration (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). A total dose of 0.05 to 250 mg of pasireotide per dose is suitable to provide a therapeutic level for 7 days to 168 days. In some embodiments, the dose 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. Clearly, the stability of the active substance and the effect on the release rate will mean that the loading and the duration may not be linearly related. 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.

[0130] In another embodiment, the pre-formulation comprises an active agent that is not an endogenous somatostatin or a somatostatin analogue. For example, the peptide active agent can be a peptide that does not interact as an agonist or antagonist at any of the SST(1) to SST(5) receptors (especially the corresponding human receptors).

[0131] In this alternative embodiment, such pre-formulations will not contain any somatostatin or somatostatin analogue active agents. That is, there are active agents that do not fall within the scope of the somatostatin analogues described in the foregoing section. In particular, in this embodiment, the pre-formulation can comprise an active agent that is not selected from endogenous somatostatin, SST-14, SST-28, octreotide, lanreotide, vapreotide or pasireotide or a salt thereof. Further, in this embodiment, endogenous somatostatin, SST-14, SST-28, octreotide, lanreotide, vapreotide or pasireotide can be completely excluded from the pre-formulation. In one embodiment, the pre-formulation is free of somatostatin, somatostatin receptor agonists and somatostatin analogues.

[0132] Other active agents that can be included in the pre-formulations of the present disclosure include:

[0133] GnRH antagonists, such as cetrorelix, ganirelix, abarelix, degarelix;

[0134] GLP-1 and its analogues, such as GLP-1(7-37), GLP-1(7-36) amide, liraglutide, semaglutide, exenatide and lixisenatide (AVE0010);

[0135] Glucagon-like peptide 2 agonists (GLP-2) and analogs thereof, such as GLP-2 and elsiglutide (ZP1846);

[0136] DPPIV inhibitors; sodium / glucose cotransporter 2 (SGLT2) inhibitors.

[0137] Other peptides suitable for the present disclosure include: angiotensin, 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, dermorphin-derived tetrapeptide (TAPS), dynorphin, endorphin, endostatin, endothelin, endothelin-1, enkephalin, epidermal growth factor, erythropoietin, fibroblast growth factor, follicle stimulating hormone, follistatin, follicle stimulating hormone, galanin, galanin-like peptide, galectin-1, gastrin, gastrin releasing peptide, G-CSF, orexin, glial cell line-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), morphiceptin, 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.

[0138] The short elimination half-lives of opioid drugs such as morphine, hydromorphone, and oxycodone require frequent administration of these agents to achieve around-the-clock analgesia, making them excellent candidates for long-acting release formulations. Fentanyl and buprenorphine undergo significant first-pass metabolism and lack sufficient bioavailability following oral administration. Along with their high potency, fentanyl and buprenorphine are excellent candidates for the long-acting injectable depot compositions of the present disclosure. Sufentanil, remifentanil, oxymorphone, dimorphone, dihydroetorphine, diacetylmorphine are other effective opioid receptor agonists suitable for the present disclosure.

[0139] Buprenorphine is also used for the maintenance treatment of opioid addiction and possibly also cocaine and amphetamine and methamphetamine addiction. Current sublingual buprenorphine formulations have low bioavailability, high variability, and limited duration of action, resulting in problems with unpredictable dose responses and withdrawal symptoms, especially in the morning. These problems are effectively addressed by using the injectable depot compositions of the present disclosure, and the problems of misuse and abuse are also addressed, where the need for high sublingual doses is eliminated by injection, and in cases where high sublingual doses are required, the same dose is significantly more effective, thus making it prone to drug misuse. Similarly, opioid antagonists can be used to treat addiction using the convenient injectable depot system provided by the present disclosure. Opioid antagonists suitable for the present disclosure are naloxone, nalmefene, and naltrexone.

[0140] Antipsychotics including risperidone, iloperidone, paliperidone, olanzapine, asenapine, ziprazidone, and aripiprazole are also well-suited for the present disclosure given the potential to improve patient treatment compliance and by providing stable plasma levels over time. Similarly, the present disclosure can be used to treat dementia, Alzheimer's disease, and Parkinson's disease that have an adverse effect on cognition. Suitable active ingredients include donepezil, rivastigmine, galantamine, memantine, rasagilin, and pramipexol.

[0141] Another group of active agents that may be included in the pre - formulations of the present disclosure are 5HT3 antagonists. 5HT3 antagonists include first - generation and second - generation 5HT3 antagonists. In one embodiment, the pre - formulation comprises a 5HT3 antagonist selected from the group consisting of ondansetron, tropisetron, granisetron, dolasetron, palonosetron, alosetron, cilansetron, and / or ramosetron or mixtures thereof. The dose of the 5HT3 antagonist suitable for inclusion in the composition and thus the volume of the pre - formulation used will depend on the release rate (e.g., controlled by the type and amount of solvent), the release duration, the desired therapeutic level, the activity of the particular agent, and the clearance rate of the particular active substance selected. Generally, an amount of 1 to 500 mg per dose is suitable to provide a therapeutic level for 5 days to 90 days. Such an amount can be 1 to 300 mg per dose. For granisetron, this level is typically around 10 to 180 mg (e.g., for 3 days to 60 days). Generally, for a depot designed to release over 30 days to 1 year, such as for a depot designed to release over 3 to 6 months, the amount of granisetron between injections will be around 0.2 to 3 mg per day. Clearly, the stability of the active substance and the linearity of the release rate will mean that the loading and the duration may not be linearly related. A depot administered every 30 days may have, for example, 2 to 30 mg of the active substance, or a 90 - day depot may have 6 to 90 mg of the active substance.

[0142] In an embodiment, the active agent is granisetron, buprenorphine, or a mixture of granisetron and buprenorphine, and their salts.

[0143] 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 (especially in humans).

[0144] Other optional components

[0145] In one embodiment, the pre - formulation comprises at least 10 ppm EDTA. Suitable pre - formulations containing, for example, amines such as ethanolamine and EDTA are described in WO 2018 / 060212 (especially pages 18 to 21), the entire document of which is incorporated herein by reference. Suitable EDTA salts that enable the presence of EDTA in the pre - formulation include tetra(ethanolammonium)EDTA or EDTA salts of ethanolamine, diethanolamine, glucosamine, tromethamine, ethylenediamine, and / or serine.

[0146] Administration

[0147] The pre-formulations of the present disclosure are generally formulated for parenteral administration, e.g., by subcutaneous injection. Such administration is generally not an intravascular method, but rather subcutaneous (s.c.), intra-cavitary or intramuscular (i.m.). Generally, administration will be by injection, which term is used herein to denote any method by which the formulation passes through the skin, such as by needle, catheter or needle-less syringe.

[0148] Preferred parenteral administration is by i.m. or s.c. injection, most preferably by s.c. injection. An important feature of the compositions of the present disclosure is that they can be administered by both i.m. and s.c. as well as other routes without toxicity or significant local effects. It is also suitable for intra-cavitary administration. The advantage of deep s.c. injection is that it is less deep and less painful to the subject compared to (deep) i.m. injection used for some current depots, and is technically most suitable for the current situation as it combines the simplicity of injection and the low risk of local side effects. Unexpectedly, the inventors have observed that the formulations provide sustained release of the active agent over a predictable period of time by both subcutaneous and intramuscular injection. Thus, this allows for wide variation in the injection site and allows dosing without detailed consideration of the tissue depth at the injection site.

[0149] In one embodiment applicable to all aspects of the present disclosure, the pre-formulations disclosed herein can be administered by an auto-injector device, e.g., an auto-injector, which generally comprises a pre-filled glass syringe or glass barrel (e.g., a glass syringe or barrel) (provided that the inner surface is free of pre-applied silicone lubricant), a mechanical or electrical device for expelling the formulation (e.g., a spring or other elastic material in a stretched or compressed state or a battery-powered motor), a trigger or switch for initiating the injection, and a needle for effecting the injection. Such an auto-injector filled with any formulation of the present disclosure will clearly form another aspect.

[0150] The preferred lipid pre-formulations of the present disclosure provide non-lamellar liquid crystalline reservoir compositions upon exposure to an aqueous fluid (especially in vivo). As used herein, the term "non-lamellar" is used to denote a normal or inverse liquid crystalline phase (such as a cubic or hexagonal phase) or an L3 phase or any combination thereof. The term liquid crystalline denotes all hexagonal, all cubic liquid crystalline phases and / or all mixtures thereof. Unless otherwise stated, hexagonal as used herein denotes the "normal" or "inverse" hexagonal (preferably inverse) phase, while "cubic" denotes any cubic liquid crystalline phase. Those skilled in the art will readily be able to determine those compositions having the appropriate phase behavior by reference to the description and examples provided herein as well as WO2005 / 117830, but the compositional region most favorable for phase behavior is for component i): the ratio of phospholipids 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 about 50:50 (e.g., ±2) is highly preferred, and most preferably about 50:50.

[0151] It is important to understand that the pre-formulations of the present disclosure have a low viscosity (e.g., as discussed herein). Thus, these pre-formulations cannot be in any bulk liquid crystalline phase, as the viscosity of all liquid crystalline phases is significantly higher than that which can be administered by syringe or similar injection dispenser. The pre-formulations of the present disclosure will thus be in a non-liquid crystalline state, such as a solution, an L2 or L3 phase, especially a solution or L2. As used throughout this specification, the L2 phase is preferably a "swollen" L2 phase containing greater than 5 wt%, preferably greater than 7%, most preferably greater than 9% of an organic monohydric alcohol solvent having a viscosity reducing effect. The pre-formulations of the present disclosure in the L2 phase form a preferred group of pre-formulations, and these pre-formulations generally contain at least 2% water as a polar solvent.

[0152] As used herein, the term "low-viscosity mixture" is used to denote a mixture that can be readily administered to a subject and, in particular, can be readily administered by means of a standard syringe and needle device. This can be indicated, for example, by the ability to dispense from a 1 ml disposable syringe through a small gauge needle. Preferably, the low-viscosity mixture can be dispensed by manual pressure through a 19-gauge needle, preferably smaller than 19-gauge, such as 22G (22-gauge), more preferably 23G (optionally even 25G or 27G or 29G) needle. In a particularly preferred embodiment, the low-viscosity mixture should be a mixture capable of passing through a standard sterile filter membrane, such as a 0.22 μm syringe filter. A typical range of suitable viscosities 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 suitable for all aspects of the present disclosure. Suitable needles include 22G UTW and 23G TW.

[0153] It has been observed that by adding a small amount of a low-viscosity organic monohydric alcohol solvent (as indicated herein), a very significant viscosity change can be provided. For example, adding only 5% of the solvent to a lipid mixture can reduce the viscosity by 100-fold, and adding 10% of the solvent can reduce the viscosity by up to 10,000-fold. In order to achieve this non-linear, synergistic effect in reducing viscosity, it is important to use a solvent with an appropriately 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.

[0154] After administration, the preferred lipid-based pre-formulations of the present disclosure undergo a phase structure transition from a low-viscosity mixture to a high-viscosity (usually tissue-adhesive) depot composition. Typically, this will be a transition from a molecular mixture, swollen L2 and / or L3 phases to one or more (high-viscosity) liquid crystalline phases, such as a forward or reverse hexagonal or cubic liquid crystalline phase or a mixture thereof. Further phase transitions may also occur after administration. Clearly, a complete phase transition is not necessary for the function of the present disclosure, but at least the surface layer of the administered mixture will form a liquid crystalline structure. Typically, for at least the surface region of the administered formulation (the part in direct contact with air, body surface, and / or body fluids), this transition will be rapid. This will most preferably occur within seconds or minutes (e.g., from 1 second to up to 30 minutes, preferably up to 10 minutes, more preferably 5 minutes or less). The remainder of the composition can more slowly undergo a phase transition to a liquid crystalline phase by diffusion and / or as the surface region disperses.

[0155] Without being bound by theory, it is believed that upon exposure to an excess of aqueous fluid, the pre-formulations of the present disclosure lose some or all of the organic solvents contained therein (e.g., by diffusion) and absorb aqueous fluid from the body environment (e.g., the in vivo environment). For lipid pre-formulations, at least a portion of the formulation preferably forms a non-lamellar, particularly liquid crystalline phase structure. In most cases, these non-lamellar structures are highly viscous and not readily soluble or dispersible into the in vivo environment. As a result, an overall "depot" is created in the body, with only limited areas being exposed to body fluids. Additionally, because non-lamellar structures have large polar, non-polar, and boundary regions, the lipid depot is very effective at solubilizing and stabilizing active agents such as peptides and protecting them from degradation mechanisms. As the depot composition formed from the pre-formulation gradually degrades over a period of days, weeks, or months, the active agent is gradually released and / or diffused out of the composition. Since the environment within the depot composition is relatively protected, the pre-formulations of the present disclosure are well-suited for active agents with a relatively low biological half-life (see above).

[0156] By incorporating at least 10% of a polar solvent (especially at least 5% water) into the pre-formulation, it is believed that the rate of phase transition to a non-lamellar (e.g., liquid crystalline) phase at the surface of the injected pre-formulation can be enhanced compared to a composition containing organic solvents in the substantial absence of water. The performance of the resulting depot is thus improved, and further control of the release of the active agent is achieved.

[0157] The depot systems formed from the formulations of the present disclosure are very effective at protecting active agents from degradation, thus allowing for an extended release period. Accordingly, the formulations of the present disclosure can provide an in vivo depot for peptide active agents, which only need to be administered once every 5 to 90 days, preferably 5 to 60 days, more preferably 6 to 32 days. Clearly, a longer sustained release period is desirable for patient comfort and compliance and requires less time from health professionals (in the case where the composition cannot be self-administered). In the case of self-administering the composition, compliance can be assisted by administering weekly (e.g., every 7 days, optionally ±1 day) or monthly (e.g., every 28 days or 30 days (optionally ±7 days)) in order not to forget the need for administration.

[0158] A significant advantage of the depot precursors of the present disclosure is that they are stable homogeneous. That is, they are capable of being stored for a relatively long time (preferably at least 6 months) at room temperature or refrigerator temperature without phase separation. In addition to providing favorable storage and convenient administration, this also allows for the selection of the dose of the peptide active agent (e.g., a somatostatin analogue, e.g., octreotide) by injecting a selected volume, with reference to the species, age, sex, body weight, and / or physical condition of the individual subject.

[0159] Accordingly, the present disclosure provides methods that include selecting a dosage amount specific to an individual (particularly selected by subject body weight). This method of dosage selection is a selection of the volume to be administered.

[0160] The pre-formulations of the present disclosure are highly advantageous because they are stable for long-term storage in their final "administration ready" form. Thus, they can be readily supplied by health professionals or patients or their caregivers for administration, and these individuals need not be highly trained health professionals and may have no experience or skill in formulating complex formulations. This is particularly important in diseases of long duration and slow onset such as diabetes.

[0161] The amount of the lipid component in the lipid-based pre-formulation is generally at least 40% by weight of the total formulation (e.g., 40% to 95%, such as 50% to 90% or 50% to 80%).

[0162] As used herein, the terms "long-term precipitate" and "visible precipitate" are used to denote insoluble precipitates (e.g., particles) in a pre-formulation (e.g., a lipid-based pre-formulation in a glass syringe or glass cartridge), which do not redissolve when the pre-formulation is equilibrated 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)) at room temperature (15°C - 25°C, e.g., 25°C). The term "refrigerated condition" is used to denote 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 pre-formulations as described herein) are subject to regulatory requirements, and the presence of particles / precipitates in formulations for parenteral (e.g., subcutaneous administration) is regulated by agencies. Glass syringes or glass cartridges containing lipid-based pre-formulations as described herein are described as (substantially) free of visible precipitates and / or turbidity (clear liquid), which can be determined according to USP <790>. Additionally, a container (syringe or cartridge) containing a lipid-based pre-formulation as disclosed herein contains no more than (NMT) 6000 particles greater than or equal to 10 μm (precipitates and / or turbidity) and / or NMT 600 particles greater than or equal to 25 μm (precipitates and / or turbidity), as determined by USP <788>. According to USP <788>, particles should be understood as "the particulate matter in injections and parenteral infusions consists of movable undissolved particles (other than air bubbles) unintentionally present in the solution", i.e., USP <788> applies to the detection and quantification of precipitates and / or turbidity. Throughout this specification and the appended claims, it should be understood that USP <788> can be substituted for USP <790> or used in combination therewith (the European equivalent of USP <788> is Ph.Eur. 2.9.19). The testing of the container can be carried out using Method 1 (Light Obscuration Test), and if such a container does not meet the specifications, Method 2 (Microscopic Particle Count) can be used to repeat the test.

[0163] The term "a glass syringe or glass cartridge containing a lipid-based pre-formulation is substantially free of visible precipitates" and the term "clear" used herein should be understood that the pre-formulation is acceptable for parenteral (such as subcutaneous) injection in a subject.

[0164] Use of a diacylglycerol composition

[0165] In one aspect, the present disclosure provides the use of a diacylglycerol composition in preventing or reducing the formation of precipitates that persist in a pre-formulation comprising i) a diacylglycerol composition according to the first aspect of the present disclosure and ii) at least one biocompatible organic solvent, wherein the fatty acid composition of the diacylglycerol composition is at least 98% oleic acid (18:1), as determined according to method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0.

[0166] 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 pre-formulation, i.e., the pre-formulation is substantially free of any diacylglycerol composition other than the diacylglycerol composition according to the first aspect of the present disclosure.

[0167] The biocompatible organic solvent component ii) is the same as the component ii) of the pre-formulation according to the first aspect of the present disclosure. Thus, the biocompatible organic solvent component ii) in the use of the present disclosure can be the same as any of the embodiments described for the biocompatible organic solvent component ii) of the pre-formulation according to the aspects of the present disclosure.

[0168] In one embodiment, the use of the diacylglycerol composition of the present disclosure is for preventing or reducing the formation of precipitates that persist in the pre-formulation when the pre-formulation 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 "cold storage" periods and conditions apply to all aspects where the context permits.

[0169] As used herein, the terms "persistent precipitate", "precipitate", "turbidity", "opalescence" are used to denote a change in the pre-formulation, e.g., a precipitate that does not redissolve when the pre-formulation is equilibrated / conditioned at room temperature (e.g., 25°C) for a period of at least one hour (e.g., 1 to 24 hours) after cold storage. An alternative conditioning method is to warm a pre-filled syringe by body temperature (e.g., by contact with the human body, such as holding the syringe in the hand) for a sufficient time for conditioning, e.g., 1 to 10 minutes before administration, or any suitable method that does not have a negative impact on the active agent and / or the lipid-based formulation. Conditioning (before injection) typically also includes turning the pre-filled syringe containing the lipid-based composition described herein through an arc of about 45° to 180° about 5 to 50 times (e.g., about 10 to 20 times) in the hand.

[0170] In another aspect, the present disclosure provides a method for preventing or reducing the formation of precipitates that persist in a pre-formulation when the pre-formulation 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 pre-formulation comprising: (i) a diacylglycerol composition; and (ii) at least one biocompatible organic solvent; the method comprising forming the pre-formulation with a diacylglycerol composition according to the first aspect of the present disclosure. In particular, the described use is in a pre-formulation as described herein in combination with a glass syringe or glass barrel that does not contain a silicone lubricant.

[0171] Pre-filled glass syringe

[0172] In one aspect, the present disclosure provides a pre-filled glass syringe pre-filled with a lipid-based formulation (as described in any of the embodiments herein) and comprising a syringe barrel having an inner surface, wherein the inner surface portion of the syringe barrel that is in constant contact with the lipid-based formulation is free of any pre-applied silicone lubricant. Unexpectedly, the inventors have determined that when preparing a pre-filled glass syringe pre-filled with a lipid-based formulation (wherein the inner surface portion of the syringe barrel that is in constant contact with the lipid-based composition is substantially free of any pre-applied lubricant), the formation of persistent precipitates in the lipid-based formulation is prevented after storage under refrigerated conditions. An alternative to the pre-filled glass syringe is a pre-filled glass barrel, e.g., suitable for an auto-injector, such as a pen.

[0173] As used herein, the term "lipid-based formulation" means any formulation that contains a lipid component. In one embodiment, the lipid-based formulation contains a diacyl lipid. In one embodiment, the lipid-based formulation contains diacylglycerol having a fatty acid composition of at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0. In one embodiment, the lipid-based formulation forms or is capable of forming at least one liquid crystalline phase structure upon contact with an excess of aqueous fluid. In one embodiment, the lipid-based formulation is a pre-formulation according to the second aspect of the present disclosure (as described in any of the embodiments herein).

[0174] In one embodiment, the prefilled glass syringe contains a lipid-based formulation comprising 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, such as 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 constrained peptide active agent. In one embodiment, the active agent is somatostatin or a somatostatin analogue, such as a somatostatin or somatostatin analogue selected from the group consisting of SST-14, SST-28, octreotide, lanreotide, pasireotide, and vapreotide or a salt thereof. In one embodiment, the active agent is octreotide or a salt thereof, preferably octreotide chloride.

[0175] As used herein, a surface that is "substantially free" of any pre-applied lubricant means a surface that is covered by any pre-applied lubricant 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.

[0176] In one embodiment, the inner surface portion of the syringe barrel that is in constant contact with the lipid-based formulation is substantially free of any pre-applied silicone lubricant.

[0177] The prefilled glass syringe of the present disclosure has a surprisingly low breakout force. The breakout force is the maximum force required to initiate the movement of the syringe plunger in opposition to the syringe barrel. It represents the force required to overcome the static friction between the syringe plunger and the syringe barrel and is thus a measure of the ease of injecting the composition.

[0178] In one embodiment, the prefilled glass syringe has a breakout 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.

[0179] Without being bound by theory, it is believed that the lipid-based formulation provides sufficient lubrication to allow the prefilled syringe to operate without excessive force in the absence of a lubricant.

[0180] As used herein, "pre-applied lubricant" refers to any lubricant that is typically applied to glass syringes to allow them to operate smoothly and with tolerably low friction. Such lubricants are well known in the art. Examples can include petroleum-based lubricants or silicone lubricants.

[0181] Drug product

[0182] As described herein, there is a need for new therapeutic options using long-term release (extended release, etc.) pharmaceutical products. An example of such a pharmaceutical product is a glass syringe or glass cartridge containing a lipid-based pre-formulation, wherein at least the inner surface of the glass syringe is in contact with the lipid-based pre-formulation and the inner surface is free of pre-applied silicone lubricant, and wherein the lipid-based pre-formulation comprises

[0183] a) 20 - 80 wt% of a diacylglycerol having a fatty acid composition of at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the composition of fatty acids by gas chromatography) of the European Pharmacopoeia 9.0;

[0184] b) 20 - 80 wt% of a phospholipid;

[0185] c) 1 - 30 wt% of a solvent;

[0186] d) a bioactive agent (e.g., requiring storage at a temperature below 10°C);

[0187] wherein a) and b) account for at least 94 wt% of the total lipid content of the lipid-based pre-formulation, and the lipid-based pre-formulation is a clear liquid (e.g., without turbidity or haziness) 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 at least one hour, as determined according to USP <790> and / or USP <788>.

[0188] When assembled into a pharmaceutical product (i.e., a glass syringe or glass cartridge containing a preformulation as described herein), different components (e.g., the glass syringe, preformulation, optional stopper described herein) are capable of storing an active agent for long-term storage, for which cryogenic storage (such as above freezing point and up to 10 °C) is necessary or desirable in order to achieve sufficient long-term stability, e.g., for at least one year or longer, thereby enabling goals that cannot be achieved by individual components alone. The complexity of the lipid-based preformulations disclosed herein, the interaction with the glass surface (especially the pre-applied silicone lubricant), injectability (e.g., injection force, pull-off force, etc.), etc. (which are required for the safe and effective administration of lipid-based preformulations containing one or more active agents for long-term release therapy) have proven challenging, especially considering the need to provide a liquid preformulation (including the active agent) that is free of precipitates and free of turbidity and / or opalescence. Thus, the glass syringes or glass cartridges and combinations of various aspects and embodiments disclosed herein enable the provision of one or more pharmaceutical products suitable for refrigerated storage and provide a lipid-based long-acting therapy (e.g., long duration) including active agents that require refrigeration.

[0189] List of Examples

[0190] 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 diacylglycerol, the diacylglycerol having two fatty acid residues, each independently having 16 - 20 carbon atoms and one or two carbon-carbon double bonds.

[0191] E2) The diacylglycerol composition according to E1, wherein the composition comprises less than 3 wt% of saturated fatty acid residues, as measured by gas chromatography (GC).

[0192] E3) The diacylglycerol composition according to E1, which comprises less than 2 wt%, such as less than 1 wt% of saturated fatty acid residues, as measured by gas chromatography (GC).

[0193] E4) The diacylglycerol composition according to E2 or E3, wherein the amount of saturated fatty acid residues in the composition is calculated according to Method C, 2.4.22 of the European Pharmacopoeia 9.0 (Determination of the composition of fatty acids by gas chromatography).

[0194] E5) The diacylglycerol composition according to E1 - E4, wherein the diacylglycerol is a mixture of 1,2-diacylglycerol and 1,3-diacylglycerol.

[0195] E6) The diglyceride composition according to E5, wherein the isomer ratio of 1,2-diglyceride to 1,3-diglyceride 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.

[0196] E7) The diglyceride composition according to E1 - E6, wherein the diglyceride is diolein.

[0197] E8) The diglyceride composition according to E1 - E7, which contains not more than 2 wt%, such as not more than 1.5 wt%, such as not more than 1 wt%, such as not more than 0.5 wt% of monoacylglycerol.

[0198] E9) The diglyceride composition according to E1 - E8, which contains not more than 2.5 wt%, such as not more than 2 wt%, such as not more than 1.5 wt% of triacylglycerol.

[0199] E10) A pre - formulation, which comprises:

[0200] i) The diglyceride composition according to any one of the preceding claims; and

[0201] ii) At least one biocompatible organic solvent;

[0202] wherein the pre - formulation forms or is capable of forming at least one liquid crystalline phase structure after contact with an excess of aqueous fluid.

[0203] E11) The pre - formulation according to E10, wherein the diglyceride composition according to any one of E1 to E9 is the only diglyceride in the pre - formulation.

[0204] E12) The pre - formulation according to E10 or E11, wherein the at least one biocompatible organic solvent is a biocompatible oxygen - containing organic solvent; such as a solvent selected from the group consisting of ethanol, N - methylpyrrolidone (NMP), propylene glycol, benzyl alcohol, DMSO, and mixtures thereof.

[0205] E13) The pre - formulation according to any one of E10 - E12, which further comprises at least one phospholipid.

[0206] E14) The pre - formulation 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.

[0207] E15) The pre - formulation according to E13 or E14, wherein the at least one phospholipid contains or consists of phosphatidylcholine.

[0208] E16) The pre - formulation according to any one of E13 - E15, wherein the ratio of diacylglycerol to phospholipid is in the range of 20:80 to 80:20, such as in the range of 60:40 to 40:60.

[0209] E17) The pre - formulation according to any one of E10 - E16, which further comprises a bioactive agent.

[0210] E18) The pre - formulation according to E17, wherein the bioactive agent requires refrigeration or the bioactive agent demands refrigeration.

[0211] E19) The pre - formulation according to E17 or E18, wherein the bioactive agent is a peptide bioactive agent, for example, a peptide bioactive agent having no more than 45, such as no more than 30 amino acid residues.

[0212] E20) The pre - formulation according to E19, wherein the peptide bioactive agent is a cyclic and / or constrained peptide bioactive agent.

[0213] E21) The pre - formulation according to E17 to E20, wherein the bioactive agent is somatostatin or a somatostatin analogue, such as a somatostatin or somatostatin analogue selected from the group consisting of SST - 14, SST - 28, octreotide, lanreotide, pasireotide, and vapreotide or a salt thereof.

[0214] E22) The pre - formulation according to E17 to E20, wherein the bioactive agent is octreotide.

[0215] E23) The pre - formulation according to E17 to E20, wherein the bioactive agent is SST - 14.

[0216] E24) The pre - formulation according to E10 to E23, which further comprises an alkylammonium salt of EDTA.

[0217] E25) Use of the diacylglycerol composition according to any one of E1 - E9 in preventing or reducing the formation of precipitates that persist in a pre - formulation, the pre - formulation comprising:

[0218] (i) The diacylglycerol composition according to any one of E1 - E9, and

[0219] (ii) At least one biocompatible organic solvent.

[0220] E26) The use according to E23, wherein in addition to the diacylglycerol composition according to any one of E1 - E9, the pre - formulation is substantially free of any diacylglycerol composition.

[0221] E27) The use according to E25 or E26, which is for preventing or reducing the formation of precipitates that persist in the pre - formulation during a period of storage of the pre - formulation at a temperature of 0 °C to 10 °C, such as 2 °C to 8 °C, for at least 24 hours, such as at least 1 month, such as at least 3 months, such as at least 6 months.

[0222] E28) The use according to E25 to E27, wherein when the pre - formulation is equilibrated for a period of one hour at room temperature, these persistently present precipitates do not redissolve.

[0223] E29) A method for preventing or reducing the formation of precipitates that persist in a pre - formulation during a period of storage of the pre - formulation at a temperature of 0 °C to 10 °C, such as 2 °C to 8 °C, for at least 24 hours, such as at least 1 month, such as at least 3 months, such as at least 6 months, the pre - formulation comprising:

[0224] (i) a diacylglycerol composition; and

[0225] (ii) at least one biocompatible organic solvent;

[0226] The method comprises forming the pre - formulation with a diacylglycerol composition according to any one of E1 to E9.

[0227] E30) The method according to E29, wherein the pre - formulation is formed with a diacylglycerol composition according to any one of E1 to E9 as the only diacylglycerol in the pre - formulation.

[0228] E31) The method according to E29 or E30, wherein when the pre - formulation is equilibrated for a period of one hour at room temperature, these persistently present precipitates do not redissolve.

[0229] E32) A pre - filled container comprising a glass cylinder and a stopper, wherein the volume is defined by the space delimited by the glass cylinder and the stopper, and wherein said volume is at least partially filled with a pre - formulation according to E10 to E24.

[0230] E33) The pre - filled container according to E32, which is a pre - filled syringe or a pre - filled cartridge.

[0231] E34) A pre - filled glass syringe pre - filled with a lipid - based formulation and comprising a syringe barrel having an inner surface, wherein the inner surface portion of the syringe barrel that is in constant contact with the lipid - based formulation is substantially free of any pre - applied lubricant.

[0232] E35) The pre-filled glass syringe according to E34, wherein the inner surface portion of the syringe barrel that is always in contact with the lipid-based formulation before use is substantially free of any pre-applied silicone lubricant.

[0233] E36) The pre-filled 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 after contact with an excess of aqueous fluid.

[0234] E37) The pre-filled glass syringe according to any one of E34 to E36, wherein the lipid-based formulation comprises a diacyl lipid.

[0235] E38) The pre-filled glass syringe according to any one of E34 to E37, wherein the lipid-based formulation comprises a diacylglycerol.

[0236] E39) The pre-filled glass syringe according to any one of E34 to E39, wherein the lipid-based formulation comprises a diacylglycerol composition according to any one of E1 to E9.

[0237] E40) The pre-filled glass syringe according to any one of E34 to E40, wherein the lipid-based formulation further comprises a bioactive agent.

[0238] E41) The pre-filled glass syringe according to E40, wherein the bioactive agent requires refrigeration.

[0239] E42) The pre-filled glass syringe according to E40 or E41, wherein the bioactive agent is a peptide active agent, such as a peptide active agent having no more than 45, such as no more than 30 amino acid residues.

[0240] E43) The pre-filled glass syringe according to E42, wherein the peptide active agent is a cyclic and / or constrained peptide active agent.

[0241] E44) The pre-filled glass syringe according to any one of E40 to E43, wherein the bioactive agent is somatostatin or a somatostatin analogue, such as a somatostatin or somatostatin analogue selected from the group consisting of SST-14, SST-28, octreotide, lanreotide, pasireotide and vapreotide or a salt thereof.

[0242] E45) The pre-filled glass syringe according to any one of E40 to E44, wherein the bioactive agent is octreotide or a salt thereof, preferably octreotide chloride.

[0243] E46) A pre-filled glass syringe according to any one of E40 to E45, wherein the lipid-based formulation is a pre-formulation according to any one of E10 to E24.

[0244] E47) A pre-filled glass syringe according to any one of E40 to E46, having a detachment 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.

[0245] E48) A pre-filled glass syringe according to any one of E40 to E46, having a detachment force between 5 and 25 N.

[0246] E49) A pre-filled glass syringe according to any one of E40 to E48, having a sliding 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.

[0247] E50) A method of administering a pre-formulation according to any one of E10 to E24 to a patient in need thereof, wherein the syringe containing the pre-formulation 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.

[0248] E51) The method according to E50, wherein the pre-formulation has no visible turbidity at the time of administration.

[0249] E52) The method according to E50 or E51, wherein the syringe is warmed at body temperature (e.g., by contact with the human body, such as by holding in the hand) for 1 to 10 minutes before administration.

[0250] 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.

[0251] E54) The method according to any one of E49 to E53, wherein the syringe is a pre-filled glass syringe according to any one of E34 to E48.

[0252] Examples

[0253] Materials

[0254] 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 were used throughout the examples:

[0255] EtOH Ethanol (99.7% European Pharmacopoeia)

[0256] GDO Glyceryl dioleate (Cithrol GDO HP-SO-(LK) from Croda)

[0257] OCT(Cl) Octreotide hydrochloride

[0258] PG Propylene glycol (European Pharmacopoeia)

[0259] SPC Soybean phosphatidylcholine (Lipoid S100 from Lipoid GmbH)

[0260] General procedure

[0261] Preparation of 1,3-diolein (1,3GDO)

[0262]

[0263] Protocol 1

[0264] One 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 equivalent of dimeric 1,3-dihydroxypropan-2-one, 0.5 equivalent of pyridine, and 0.25 equivalent of DMAP. The reaction mixture was maintained at 20 °C for 15 h, then the pyridinium hydrochloride formed was removed by filtration and washed with dichloromethane. The combined organic matter was washed with 5% sodium chloride, 5% sodium carbonate, 0.1 M hydrochloric acid, and then again with 5% sodium chloride. The solution was dried and evaporated to give a semi-solid, which was triturated with methanol and then refrigerated overnight. The solid collected was recrystallized from isopropyl ether and methanol to give 2-oxopropane-1,3-dioleate (98.5% HPLC purity).

[0265] The 2-oxopropane-1,3-dioleate obtained was dissolved in 500 ml of tetrahydrofuran, and after the stepwise addition of sodium borohydride, 20 ml of water was added, followed by cooling to 5 °C, and the temperature was maintained at about 5 °C - 10 °C. The reaction was monitored by HPLC, and after completion of the reaction, the addition of sodium borohydride was stopped, the solvent was removed, and the residue was partitioned 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 give 1,3-diolein (98.5% HPLC purity).

[0266] Isomerization of 1,3GDO

[0267] In the presence of a protic solvent, 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, and the mixture is heated to about 70 °C for 24 hours to achieve a ratio of about 1.9 (1,3-GDO / 1,2-GDO). Optionally, in the presence of 50% ethanol and at 40 °C, 1,3-diolein is allowed to reach equilibrium within 4 days.

[0268] The obtained mixture of 1,2-diolein and 1,3-diolein has a purity of 98% and not more than (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 Method C, 2.4.22. (Determination of the composition of fatty acids by GC) of the European Pharmacopoeia 9.0 (expressed as the percentage of the peak area of the corresponding methyl esters), i.e., the fatty acid composition contains at least 98% oleic acid (18:1).

[0269] Example 1: Storage stability of a pre-formulation containing a diacylglycerol composition

[0270] A lipid stock solution is prepared by weighing in soy phosphatidylcholine (SPC), a mixture of 1,2-diolein and 1,3-diolein (GDO) prepared as above, ethanol (EtOH) and propylene glycol (PG), and inverted and mixed until homogeneous. The final formulation is prepared by adding the lipid stock solution to the weighed octreotide chloride (OCT(Cl)) powder, then flushing the vial with nitrogen and inverting and mixing until homogeneous. The formulation is then sterile filtered at 3 bar pressure, subsequently aliquoted into vials, and finally flushed with nitrogen. Filling of pre-filled syringes is carried out by adding about 0.5 g of the formulation to each syringe using a disposable pipette under ambient air and temperature conditions. A stopper (e.g., a commercially available stopper from BD or West) is placed in position using a plunger rod (which is subsequently separated) with the aid of a wire. Bubbles (air) in the syringe are minimized as much as possible. The syringes are then placed in a climate chamber, and samples are withdrawn at specified time points for visual inspection and HPLC analysis. All syringes are pre-lubricated with silicone oil, e.g., commercially available 1 mL glass syringes such as those sold by the Gerresheimer Group, Schott AG and BD. The comparative composition is prepared as above, except that commercially available GDO (Cithrol GDO HP-SO-(LK) from Croda) is used instead of the disclosed GDO prepared as above.

[0271] In addition, samples (3 - 10) were prepared using a similar procedure (but including other excipients and optionally not including the active agent (octreotide chloride)) and are included in Table 1.

[0272] Table 1: Composition (wt%)

[0273]

[0274] *Control

[0275] **Fatty acid composition containing at least 98% oleic acid (18:1)

[0276] The samples were stored under refrigerated conditions at 2°C - 8°C, 15°C, 25°C / 60% RH, and 40°C / 75% RH.

[0277] On day 0, and after 1 month, 3 months, 6 months, 12 months, and 14 months, extracts were taken from Samples 1 - 10. Throughout the test period, the extracts from the samples stored at 15°C, 25°C / 60% RH, and 40°C / 75% RH remained clear and homogeneous. The extracts from the samples stored at 2°C - 8°C were frequently frozen and examined visually and under polarized light. The examination results of the samples stored under refrigerated conditions are presented in Table 2.

[0278] Table 2:

[0279] Sample No.: Day 0 1 month 3 months 6 months 12 months 14 months 1* Pass Pass Fail Fail Fail Fail 2 Pass Pass Pass Pass Pass Pass 3* Pass Pass Fail Fail Fail Fail 4 Pass Pass Pass Pass Pass Pass 5* Pass Fail Fail Fail Fail Fail 6 Pass Fail Fail Fail Fail Fail 7* Pass Pass Pass Pass Fail Fail 8 Pass Pass Pass Pass Pass Pass 9* Pass Pass Fail Fail Fail Fail 10 Pass Pass Pass Pass Pass Pass

[0280] *Control

[0281] Examination of the refrigerated extracts revealed that the formulations prepared using conventional GDO contained precipitates after thawing, and / or the samples showed turbidity or opalescence. The precipitates appeared to be granular crystals distributed near the stopper and the glass wall.

[0282] Figure 1 Shown are pre - filled syringes photographed under polarized light, pre - filled with Sample 2 stored at 5°C for 14 months. These photos were taken 0 minutes, 5 minutes, 15 minutes, and 30 minutes after removal from the climatic chamber. Note that the white dots observed in the background do not exist in the formulation, and the formulation appears completely transparent within 15 min of equilibration at RT.

[0283] Analysis of other samples (3 - 10) stored at 2 °C - 8 °C showed the presence of precipitates, which usually (but not always) redissolved within a few hours at room temperature. However, in some samples, a large amount of precipitate, turbidity, and / or opalescence still remained. Some samples stored at 5 °C and 15 °C showed opalescence when examined at room temperature conditions for one hour. Opalescence was generally more pronounced in the control samples. Table 2 represents "failures" when the sample contained precipitate, or failed due to other obvious reasons such as excessive turbidity, opalescence (which is not considered a complete failure). Thus, Example 1 illustrates the use of diacylglycerol that provides substantial improvement after storage under refrigerated conditions, the fatty acid composition of which is at least 98% oleic acid (18:1), as determined according to Method C, 2.4.22 (Determination of the fatty acid composition by gas chromatography) of the European Pharmacopoeia 9.0. Some samples developed opalescence, which spurred further exploration to provide consistent lipid - based formulations that can be used for low - temperature storage (such as between 2 °C - 8 °C).

[0284] HPLC analysis of the extracts from Samples 1 and 2 showed that the active agents in all samples were within the specifications, and refrigeration slowed down the degradation of the active agents, such that more than 90% of the original content was retained, indicating longer storage stability.

[0285] Example 2 - Exploration of Turbidity and Opalescence

[0286] Turbidity and / or opalescence appeared in some of the samples prepared in Example 1. Although when examining pre - formulations stored under refrigerated conditions in glass vials, which were identical to those in Example 1, it was surprisingly noted that the pre - formulations did not show opalescence under visual inspection. In contrast to syringes, glass vials do not contain pre - applied lubricant (silicone oil). Generally, glass syringes are treated with lubricants such as silicone oil to achieve acceptable injection force, thus allowing for self - administration, for example, and ensuring compatibility with auto - injectors (e.g., considering injection time). To develop acceptable lipid - based formulations suitable for storage under refrigerated conditions, further studies were conducted.

[0287] Prepare the following pre - formulations without active agents as described in Example 1, and fill approximately 0.2 mL into 1 - mL glass syringes without pre - applied silicone oil. Seal the syringes with a plunger (such as a suitable plunger sold by BD or West).

[0288] Table 3

[0289]

[0290]

[0291] *Conventional pre-lubricated glass syringe (silicone oil)

[0292] 1 Comparison

[0293] 2 Fatty acid composition containing at least 98% oleic acid (18:1)

[0294] 3 Citrate buffer containing 0.5 mg / mL sodium EDTA

[0295] 4 Substantially anhydrous system, in which EDTA is dissolved in the lipid system by using ethanolamine (ETA), for example, visually evaluating the samples as described in Example 1 as described in WO 2018 / 060213, for example, samples 11 - 14 stored at 2 °C - 8 °C for 16 months, then visually inspected, and the results are presented in Table 4 and Figure 4 and Figure 5 in

[0296] Table 4:

[0297]

[0298]

[0299] Samples 11 and 12 contained precipitates and were unacceptable. Sample 13 was considered acceptable for administration at the first observation, while sample 14 still showed opalescence throughout the evaluation.

[0300] Example 3 - Determining the force required for injection.

[0301] Typical injection devices deliver a force of up to about 20 - 25 N. To determine the appropriate configuration of formulation, needle, volume, injection mechanism, and injection time, appropriate samples can be used for research. The method based on ISO 11040 is suitable. Needle characterization is carried out according to ISO 9626:2016.

[0302] A pre-filled syringe containing 1 ml of a lipid controlled-release formulation (placebo or containing an active agent) and free of silicone lubricant (unsiliconeized) was placed in a materials tester with a 100 N load cell. The plunger rod was installed without moving the plunger stopper (lubricated) to avoid affecting the "breakaway force" measurement. After removing the needle cap, the test was performed at a selected speed to provide correct dosing over a specified period. The necessary loading was measured over time until the plunger stopper contacted the shoulder of the syringe barrel, at which point the test was stopped. The breakaway force was determined using the maximum force in the force plot in the stroke range from 0 mm to ≤5 mm, and the sliding force was calculated based on the average force between the end of the breakaway period and just before the end of the plunger stroke. Alternatively, the sliding force was calculated using the maximum force from just after the end of the breakaway period to just before the end of the plunger stroke.

[0303] Testing of the lipid controlled-release formulations has shown that such formulations are closely related to the established Hagen-Poiseuille theory. In this theory, the injection time is linearly related to the viscosity, needle length, and fill volume; the 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.

[0304] Since the formulations fit well with the Hagen-Poiseuille theory, it is possible to calculate the average delivery force (sliding force) required for various viscosities, delivery times, and needle diameters and develop a model. Examples based on the developed model are shown in the table below.

[0305]

[0306] Figure 2a (22G extra thin wall) and Figure 2b (23G thin wall) show the variation of injection time with sliding force for various viscosities in the range from 100 to 1000 mPas.

[0307] The breakaway force is defined as the maximum force for the plunger stopper moving within the range from 0 mm to ≤5 mm inside the syringe barrel. The breakaway force of the above pre-filled syringe containing 1 ml of a lipid controlled-release formulation results in a good combination of breakaway force and estimated sliding force, i.e., as disclosed in Figure 3 and is considered suitable for self-administration or for use with an auto-injector.

[0308] A comparative test was conducted using a corresponding empty syringe without silicone lubricant. The test was stopped because a force of 45 N was not sufficient to provide the breakaway force and sliding force required to inject 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 breakaway force can be analyzed according to ISO11040-4:2015 (Glass Syringes for Injectables).

[0309] A similar test was conducted using an unsiliconeized syringe (which had a barrel containing water, was equipped with a 22G UTW needle, and an unlubricated stopper). A force of 45 N was reached without complete injection of air.

[0310] This test was repeated using an unsiliconeized syringe barrel filled with water, a 22G UTW needle, and a silicone-lubricated stopper. The results showed that it was possible to inject into air using an unsiliconeized barrel but a siliconeized stopper, but a large force was required. Breakaway forces of approximately 13, 20, and 18 N were obtained (plunger strokes of 0.5, 1, and 5 mm / s), and these values were considered high considering the low viscosity of water.

[0311] Filling a non-lubricated syringe with the lipid composition disclosed herein did meet the requirements for breakaway force as well as sliding force. Thus, it was found that a syringe sealed with a plunger stopper (preferably lubricated), filled with a lipid composition as disclosed herein, and without lubricating silicone oil, could be stored for an extended period at 2°C - 8°C without visible precipitation and / or turbidity, such as opalescence, upon restoration to room temperature. Furthermore, such pre-filled syringes do not require an excessive injection force in order to inject a specific amount (e.g., 0.1 - 3 ml) of the lipid composition within an acceptable period (such as 3 - 25 s, such as 5 - 20 s, such as 5 - 15 s). Examples of the force allowed for plunger injection of the formulation are 5 - 25 N, such as 8 - 20 N. The pre-filled syringes described herein do meet the overall objective of enabling low-temperature storage of syringes containing active agents that require such low-temperature storage (e.g., 2°C - 8°C), while injectability and product consistency (no precipitation and clear liquid) are achieved through 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 is free of pre-applied silicone lubricant, the at least inner surface of the glass syringe or glass barrel is free of pre-applied lubricant, and wherein the lipid-based preformulation comprises a) 20 - 80 wt% of diacylglycerol, the fatty acid composition of which is at least 98% oleic acid (18:1), determined according to method C, 2.4.22 of the European Pharmacopoeia 9.0; b) 20 - 80 wt% of phospholipids; c) 1 - 30 wt% of a solvent; d) GLP-1 and its analogs; 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 at least one hour, determined according to USP <790>.

2. The glass syringe or glass barrel according to 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 at least one hour, determined according to USP <790>.

3. The glass syringe or glass barrel according to 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 at least one hour, determined according to USP <790>.

4. The glass syringe or glass barrel according to claim 1, the preformulation containing: not more than (NMT) 6000 particles greater than or equal to 10 μm and / or NMT 600 particles greater than or equal to 25 μm, determined by USP <788>.

5. The glass syringe or glass barrel according to any one of claims 1 - 4, wherein the diacylglycerol contains not more than 2 wt% of monoacylglycerol.

6. The glass syringe or glass barrel according to any one of claims 1 - 5, wherein the preformulation contains not more than 5 wt% of triacylglycerol.

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

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

9. The glass syringe or glass barrel according to any one of claims 1 - 8, wherein the ratio of diacylglycerol 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 1-9, wherein a) and b) account for at least 95 wt% of the total lipid content of the said pre-formulation.

11. The glass syringe or glass barrel according to any one of claims 1-10, 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 1-11, 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 1-12, wherein the GLP-1 analog is selected from GLP-1(7-37), GLP-1(7-36) amide, liraglutide, semaglutide, exenatide, and lysine exenatide (AVE0010).

14. The glass syringe or glass barrel according to any one of claims 1-13, wherein the GLP-1 analog is semaglutide.

15. The glass syringe or glass barrel according to any one of claims 1-14, which is stored for at least 1 month.

16. The glass syringe or glass barrel according to any one of claims 1-15, which is free of visible precipitate and / or turbidity after equilibration for a period of one hour at room temperature.

17. The glass syringe or glass barrel according to any one of claims 1-16, which contains 0.1 to 3 ml of the said lipid-based pre-formulation.

18. The glass syringe or glass barrel according to any one of claims 1-17, wherein the plunger sealing the syringe or barrel has a release force of not more than 35 N.

19. The glass syringe or glass barrel according to any one of claims 1-17, wherein the plunger sealing the syringe or barrel has a sliding force of not more than 35 N.

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