Patent Description:
Many pharmacologically active substances including macromolecular biopharmaceuticals such as peptides, proteins, nucleic acids, and viruses, as well as small-molecular synthetic compounds, especially those with short residence time in the body should be administered repeatedly within a short period of time in order to maintain the therapeutically effective concentration thereof. Such repeated administration may lead to a decrease in patient compliance, an increase in maximum blood concentration due to repeated administration and an increase in side effects thereby, and inappropriate therapeutic effects. There have been studied various methods which are applicable to oral and parenteral dosage forms for sustained release of pharmacologically active substances, in order to improve these problems. For example, there have been suggested oral formulations such as sustained-release tablets using polymers and gastric retention tablets and parenteral formulations such an extended release preparation through the skin (e.g., a transdermal patch) and an injectable preparation (e.g., subcutaneous implantation tablets, liposomes, and microspheres).

For injectable formulations for sustained release of drug, there have been mainly studied the formulations that can be administered intramuscularly or subcutaneously. Injectable formulations for sustained release of drug continuously release a physiologically active substance through single administration for several days to several weeks or months, thereby being able to maintain a therapeutically effective concentration of a drug for a long period of time and prevent side effects due to repeated administration. Most of the injectable formulations for sustained release of drug, from which the release of drug lasts for several days or more, are a formulation designed to form a drug-depot in the body and gradually release the drug into the systemic circulation. Representatively, there have been suggested a formulation in which a pharmacologically active substance is encapsulated into PLGA (a biodegradable polymer) microspheres. The microspheres are gradually decomposed into lactic acid and glycolic acid in the body, which results in slow release of the active ingredient. Polycyanamide, as well as PLGA, is also used as a biodegradable polymer used for the preparation of microspheres. Sustained-release microsphere formulations made of a biodegradable polymer induce sustained release of a drug, thereby being able to prolong the drug's efficacy. However, biodegraded polymer particles may bring about inflammation at the injection site. Since it is also difficult to use a conventional sterile filtration method (which is one of the most industrially convenient methods) in the process for preparing a sterile formulation necessary for injection, there exists the disadvantage that it should be manufactured in a special manufacturing equipment, e.g., in a closed aseptic processing system for sterilization.

As a formulation capable of circumventing the disadvantages of biodegradable polymer-based formulations, <CIT> discloses a liquid depot formulation comprising at least one neutral diacyl lipid (e.g., diacyl glycerol such as glyceryl dioleate) and/or at least one tocopherol; at least one phospholipid; and at least one biocompatible, oxygen containing, low-viscosity organic solvent. However, formulations containing neutral diacyl lipids, such as glyceryl dioleate, have a problem of low biodegradability. And, since neutral diacyl lipids are not a material derived from the body, their biocompatibility is limited and there is a high possibility of causing inflammation.

<CIT> discloses a sustained release lipid pre-concentrate comprising a sorbitan unsaturated fatty acid ester; a phospholipid such as phosphatidylcholine; and a liquid crystal hardener, free of an ionizable group (such as carboxyl group or amine group), having a hydrophobic moiety of <NUM> to <NUM> carbon atoms with a triacyl group or a carbon ring structure. And, <CIT> discloses a sustained release lipid pre-concentrate comprising a sorbitan unsaturated fatty acid ester; a phospholipid such as phosphatidylcholine; a liquid crystal hardener such as triglyceride and tocopherol acetate; and an anionic anchoring agent such as palmitic acid. However, since sorbitan monooleate has a high viscosity (about <NUM> mPa. s, <NUM>), the formulation obtained by using the same also has a high viscosity, which leads to a problem of showing low injectability. And, sorbitan monooleate is not a component of the body nor a material derived from the body and thus may cause safety problems, e.g., inflammation at the site of administration. <CIT> discloses a sustained-release lipid pre-concentrate comprising a liquid crystal former which is a surfactant, a neutral phospholipid, a liquid crystal hardener and an anionic anchoring agent.

Therefore, there is a need in the art to develop a sustained-release injectable pharmaceutical composition which is able to prevent the initial release of drug and has excellent biodegradability, biocompatibility and injectability, as an injectable formulation that provides sustained release of a drug for more than one week.

The present inventors carried out various studies to develop a sustained-release injectable pharmaceutical composition in the form of a lipid solution having excellent biodegradability, biocompatibility and injectability. As the results thereof, the present inventors have found that, when a pre-formulation (i.e., pre-concentrate) is prepared by combining an unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>) (that is present in or derived from the body and is effectively biodegradable) with phospholipid and α-tocopherol acetate, instead of diacyl glycerol and/or sorbitan unsaturated fatty acid ester, and then is subject to formulation processes together with a pharmacologically active substance, it is possible to obtain a sustained-release injectable pharmaceutical composition in the form of a lipid solution having excellent injectability, biocompatibility and biodegradability.

Therefore, it is an object of the present invention to provide a sustained-release lipid pre-concentrate in the form of a lipid solution, comprising a combination of an unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); a phospholipid; and α-tocopherol acetate.

It is another object of the present invention to provide a sustained-release injectable pharmaceutical composition in the form of a lipid solution comprising a pharmacologically active substance; and the pre-concentrate.

In accordance with an aspect of the present invention, there is provided a sustained-release lipid pre-concentrate in the form of a lipid solution, comprising an unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); a phospholipid; and α-tocopherol acetate, wherein the sustained-release lipid pre-concentrate is free of diacyl glycerol and sorbitan unsaturated fatty acid ester; and forms a liquid crystal in an aqueous medium.

In the pre-concentrate of the present invention, the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>), the phospholipid, and the α-tocopherol acetate may be present in an amount ranging from <NUM> to <NUM> wt%, in an amount ranging from <NUM> to <NUM> wt%, and in an amount ranging from <NUM> to <NUM> wt%, based on the total weight, respectively.

The pre-concentrate of the present invention may further comprise one or more organic solvents selected from the group consisting of ethanol, propylene glycol, N-methylpyrrolidone, and benzyl alcohol; or an aqueous solution of the organic solvent as a biocompatible solvent. The biocompatible solvent may be present in an amount ranging from <NUM> to <NUM> wt% based on the total weight thereof. In an embodiment, the pre-concentrate of the present invention may comprise <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; and <NUM> to <NUM> wt% of the biocompatible solvent.

The pre-concentrate of the present invention may further comprise a medium chain triglyceride. The medium chain triglyceride may be present in an amount ranging from <NUM> to <NUM> wt% based on the total weight thereof. In an another embodiment, the pre-concentrate of the present invention may comprise <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; and <NUM> to <NUM> wt% of the medium chain triglyceride. In still an another embodiment, the pre-concentrate of the present invention may comprise <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; <NUM> to <NUM> wt% of the medium chain triglyceride; and <NUM> to <NUM> wt% of the biocompatible solvent.

In accordance with another aspect of the present invention, there is provided a sustained-release injectable pharmaceutical composition in the form of a lipid solution, comprising a pharmacologically active substance; and the pre-concentrate as claimed in any one of appended claims <NUM> to <NUM>, wherein the sustained-release injectable pharmaceutical composition is free of diacyl glycerol and sorbitan unsaturated fatty acid ester.

In the pharmaceutical composition of the present invention, the pharmacologically active substance may have a solubility of <NUM>/ml or more in the pre-concentrate, for example leuprolide or a pharmaceutically acceptable salt thereof; goserelin or a pharmaceutically acceptable salt thereof; entecavir or a pharmaceutically acceptable salt thereof; a somatostatin analogue or a pharmaceutically acceptable salt thereof; a glucagon-like peptide-<NUM> (GLP-<NUM>) analogue or a pharmaceutically acceptable salt thereof; dutasteride or a pharmaceutically acceptable salt thereof; donepezil or a pharmaceutically acceptable salt thereof; aripiprazole or a pharmaceutically acceptable salt thereof; paliperidone or a pharmaceutically acceptable salt thereof; or risperidone or a pharmaceutically acceptable salt thereof.

In an embodiment, the pharmaceutical composition of the present invention may comprise <NUM> to <NUM> wt% of the pharmacologically active substance; <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; and <NUM> to <NUM> wt% of α-tocopherol acetate. In another embodiment, the pharmaceutical composition of the present invention may comprise <NUM> to <NUM> wt% of the pharmacologically active substance; <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; and <NUM> to <NUM> wt% of the biocompatible solvent. In still another embodiment, the pharmaceutical composition of the present invention may comprise <NUM> to <NUM> wt% of the pharmacologically active substance; <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; <NUM> to <NUM> wt% of the medium chain triglyceride; and <NUM> to <NUM> wt% of the biocompatible solvent.

The sustained-release lipid pre-concentrate in the form of a lipid solution according to the present invention; and the sustained-release injectable pharmaceutical composition in the form of a lipid solution comprising the same have a low viscosity, and thus exhibit superior injectability, in comparison with conventional pre-concentrates and sustained-release pharmaceutical compositions comprising the same. Especially, the sustained-release lipid pre-concentrate in the form of a lipid solution according to the present invention; and the sustained-release injectable pharmaceutical composition in the form of a lipid solution comprising the same comprise an unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>) that is present in or derived from the body and is effectively biodegradable, instead of diacyl glycerol and sorbitan unsaturated fatty acid ester, and thus exhibit excellent biocompatibility and biodegradability, thereby being able to fundamentally avoid the possibility of inflammation at the site of administration which is one of the disadvantages of conventional sustained-release injectable formulations. Therefore, the present invention can provide a pharmaceutical composition in the form of a sustained release injectable formulation having excellent safety, which is capable of providing extended release for at least <NUM> days. In addition, the sustained-release lipid pre-concentrate in the form of a lipid solution according to the present invention; and the sustained-release injectable pharmaceutical composition in the form of a lipid solution comprising the same can be easily prepared through performing various sterile processes, including sterile filtration and the like.

The present invention provides a sustained-release lipid pre-concentrate in the form of a lipid solution, comprising an unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); a phospholipid; and α-tocopherol acetate, wherein the sustained-release lipid pre-concentrate is free of diacyl glycerol and sorbitan unsaturated fatty acid ester; and forms a liquid crystal in an aqueous medium.

As used herein, the term "pre-concentrate" refers to a formulation having the form of a lipid solution, which forms a porous liquid crystal matrix having a large amount of pores of <NUM> or less, preferably <NUM> to <NUM>, therein, when exposed to an excess of aqueous medium (including water, biological fluid, etc.).

In the pre-concentrate of the present invention, the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>), which is one of the components present in the human body, plays a role in forming a porous liquid crystal matrix having a large amount of pores in nanometer units (<NUM> or less, preferably <NUM> to <NUM>) in an aqueous medium, together with a phospholipids. Saturated fatty acids have a low ability to form a liquid crystal matrix in an aqueous medium. And, saturated fatty acids having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>) exist in a solid form at room temperature and show high viscosity when prepared into a pre-concentrate, which leads to low injectability. However, it has been found by the present invention that unsaturated fatty acids having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>) exist in a liquid form at room temperature and show high liquid crystal matrix forming ability in an aqueous medium. In terms of excellent biocompatibility and liquid crystal forming ability, the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>) may be preferably oleic acid, linoleic acid, myristoleic acid, palmitoleic acid, <NUM>-eicosenoic acid, or a mixture thereof, more preferably oleic acid, linoleic acid, or a mixture thereof, and still more preferably oleic acid. The unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>), which is an unsaturated fatty acid having one or two double bonds, is a component derived from the body which is widely present in animals and plants and has excellent biocompatibility and biodegradability. The unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>), including oleic acid, linoleic acid, myristoleic acid, palmitoleic acid, and <NUM>-eicosenoic acid, rapidly forms a lipid solution having low-viscosity, thereby being able to provide excellent injectability. That is, when the pre-concentrate of the present invention is contacted with an excess of aqueous phase, it is possible to form a robust liquid crystal matrix within <NUM> hour, preferably within about <NUM> minutes. In addition, the pre-concentrate of the present invention have a low viscosity (e.g., <NUM> mPa. s or less, preferably <NUM> mPa. s or less) at room temperature (about <NUM>), so that they can be easily introduced into a living body through a <NUM> to <NUM> gauge syringe. The unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>) may be present in an amount ranging from <NUM> to <NUM> wt% based on the total weight thereof. When the amount of the unsaturated fatty acid is less than <NUM> wt% or exceeds <NUM> wt% based on the total weight of the pre-concentrate, the liquid crystal forming ability may be significantly reduced when injected into the living body and the sustained release ability of the active ingredient may be lowered; and thus it may be difficult to show the release-controlling ability for more than a week.

The phospholipid, together with the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>), plays a role in forming a liquid crystal matrix having pores in nanometer units that can serve as a drug-depot in an aqueous medium, and plays a role in helping the solubilization of a pharmacologically active substance. The phospholipid, which contains a polar head group and two nonpolar tail groups, includes variously-derived or synthetic phospholipids, such as phospholipids derived from soybean or egg yolk. The phospholipid may be phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, or a synthetic derivative thereof (e.g., dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, etc.), and include a mixture of one or more thereof. Preferably, the phospholipid may be phosphatidylcholine derived from egg yolk or soybean. The phospholipid may be present in an amount ranging from <NUM> to <NUM> wt% based on the total weight thereof. When the amount of the phospholipid is less than <NUM> wt% based on the total weight of the pre-concentrate, it may be difficult to form a liquid crystal upon injection into the body, and the ability to control extended release may be reduced. When the amount of the phospholipid exceeds <NUM> wt% based on the total weight of the pre-concentrate, the ability to form a liquid crystal may be also lowered and the ability to control drug release may be deteriorated due to formation of lamellar spheres.

The α-tocopherol acetate helps to keep the internal structure of the liquid crystal strong (i.e., stiffening), and plays a role in delaying the release rate of a pharmacologically active substance. The α-tocopherol acetate includes D-α-tocopherol acetate, DL-α-tocopherol acetate, or a mixture thereof. The α-tocopherol acetate may be present in an amount ranging from <NUM> to <NUM> wt% based on the total weight thereof.

The pre-concentrate of the present invention may further comprise a biocompatible solvent, if necessary. The biocompatible solvent includes a solvent that can be introduced into the human body in the form of an injectable formulation, for example, one or more organic solvents selected from the group consisting of ethanol, propylene glycol, N-methylpyrrolidone, and benzyl alcohol; or an aqueous solution of the organic solvent, but not limited thereto. Preferably, the biocompatible solvent may be ethanol or an aqueous solution of ethanol. The biocompatible solvent serves to improve solubilization or injectability of an active ingredient. When the pre-concentrate containing a biocompatible solvent is injected into the body, the solvent will be diluted and removed by the biological fluid during the formation of a liquid crystal in the form of a sustained-release depot. The biocompatible solvent may be present in an amount ranging from <NUM> to <NUM> wt% based on the total weight thereof. In an embodiment, the pre-concentrate of the present invention may comprise <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; and <NUM> to <NUM> wt% of the biocompatible solvent.

The pre-concentrate of the present invention may further comprise a medium-chain triglyceride, if necessary. The medium chain triglyceride helps to maintain the internal structure of the liquid crystal, and also serves to further lower the viscosity of the pre-concentrate and the pharmaceutical composition comprising the same. The medium chain triglyceride is composed of <NUM> molecules of fatty acids having <NUM> or <NUM> carbon atoms and <NUM> molecule of glycerol. The medium chain triglyceride includes, for example, tricaproin, tricaprylin, tricaprin, trilaurin, or a mixture thereof, but not limited thereto. The medium chain triglyceride may be present in an amount ranging from <NUM> to <NUM> wt% based on the total weight thereof. In an embodiment, the pre-concentrate of the present invention may comprise <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; and <NUM> to <NUM> wt% of the medium chain triglyceride. In another embodiment, the pre-concentrate of the present invention may comprise <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; <NUM> to <NUM> wt% of the medium chain triglyceride; and <NUM> to <NUM> wt% of the biocompatible solvent.

The pre-concentrate of the present invention does not comprise diacyl glycerol and sorbitan unsaturated fatty acid ester. Examples of the diacyl glycerol include glyceryl dipalmitate, glyceryl phytanoate, glyceryl palmitoleate, glyceryl distearate, glyceryl dioleate, glceryl dielaidiate, glyceryl dilinoleate, and the like. Examples of the sorbitan unsaturated fatty acid ester include sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate, sorbitan sesquioleate, sorbitan sesquilinoleate, sorbitan sesquipalmitoleate, sorbitan sesquimyristoleate, sorbitan dioleate, sorbitan dilinoleate, sorbitan dipalmitoleate, sorbitan dimyristoleate, and the like. The pre-concentrate of the present invention does not contain any of the above-mentioned diacyl glycerol and sorbitan unsaturated fatty acid ester.

The present invention also provides a sustained-release injectable pharmaceutical composition in the form of a lipid solution, comprising a pharmacologically active substance; and the pre-concentrate as claimed in any one of claims <NUM> to <NUM>, wherein the sustained-release injectable pharmaceutical composition is free of diacyl glycerol and sorbitan unsaturated fatty acid ester.

In the pharmaceutical composition of the present invention, the pharmacologically active substance (active pharmaceutical ingredient) may be a drug having a solubility of <NUM>/ml or more in the pre-concentrate. The pharmacologically active substance having a solubility of less than <NUM>/ml in the pre-concentrate leads to the increase in injection volume of the sustained-release injectable formulation and thus may induce high injection pain and be difficult to prepare a sustained-release formulation. Examples of the pharmacologically active substance having a solubility of <NUM>/ml or more in the pre-concentrate include leuprolide or a pharmaceutically acceptable salt thereof (e.g., leuprolide acetate); goserelin or a pharmaceutically acceptable salt thereof (e.g., goserelin acetate); entecavir (including monohydrate thereof) or a pharmaceutically acceptable salt thereof; a somatostatin analogue (e.g., octreotide, lanreotide, and pasireotide) or a pharmaceutically acceptable salt thereof; a glucagon-like peptide-<NUM> (GLP-<NUM>) analogue (e.g., exenatide, liraglutide, albiglutide, lixisenatide and semaglutide) or a pharmaceutically acceptable salt thereof; dutasteride or a pharmaceutically acceptable salt thereof; donepezil or a pharmaceutically acceptable salt thereof; aripiprazole or a pharmaceutically acceptable salt thereof; paliperidone or a pharmaceutically acceptable salt thereof; or risperidone or a pharmaceutically acceptable salt thereof, and the like, but not limited thereto. In an embodiment, the pharmacologically active substance may be gonadotropin-releasing hormone (GnRH) derivative, for example, leuprolide or a pharmaceutically acceptable salt thereof (e.g., leuprolide acetate); or goserelin or a pharmaceutically acceptable salt thereof (e.g., goserelin acetate). The pharmacologically active substance may be included in a therapeutically effective amount in the pharmaceutical composition of the present invention. For example, the pharmacologically active substance may be included in an amount ranging from <NUM> to <NUM> wt%, preferably from <NUM> to <NUM> wt%, based on the total weight of the composition.

In an embodiment, the pharmaceutical composition of the present invention comprises <NUM> to <NUM> wt% of the pharmacologically active substance; <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; and <NUM> to <NUM> wt% of α-tocopherol acetate. In another embodiment, the pharmaceutical composition of the present invention comprises <NUM> to <NUM> wt% of the pharmacologically active substance; <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; and <NUM> to <NUM> wt% of the biocompatible solvent. In still another embodiment, the pharmaceutical composition of the present invention comprises <NUM> to <NUM> wt% of the pharmacologically active substance; <NUM> to <NUM> wt% of the unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); <NUM> to <NUM> wt% of the phospholipid; <NUM> to <NUM> wt% of α-tocopherol acetate; <NUM> to <NUM> wt% of the medium chain triglyceride; and <NUM> to <NUM> wt% of the biocompatible solvent.

The sustained-release lipid pre-concentrate in the form of a lipid solution according to the present invention; and the sustained-release injectable pharmaceutical composition in the form of a lipid solution comprising the same may be subjected to a conventional sterile process, for example, sterile filtration using a membrane filter.

The present invention will be described in further detail with reference to the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Sustained-release lipid pre-concentrates were prepared according to the components and amounts shown in Tables <NUM> to <NUM>. The amounts of Tables <NUM> to <NUM> represent the weight percent (wt%) of each component in the sustained-release lipid pre-concentrate. Specifically, soybean-derived phosphatidylcholine or phosphatidylethanolamine, unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>) (oleic acid, linoleic acid, myristoleic acid, palmitoleic acid, or <NUM>-eicosenoic acid), DL-α-tocopherol acetate, medium chain triglyceride [Kollisolv™ MCT <NUM> (a mixture of tricapryline and tricaprine, about <NUM>:<NUM> of weight ratio), BASF], and/or biocompatible solvent (ethanol, propylene glycol, or N-methylpyrrolidone) were added to a glass vial; and then mixed under stirring at room temperature with a magnetic stirrer. Each resulting mixture was homogenized at room temperature with a homogenizer (POLYTRON PT1200E, KINEMATICA) under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes, and then left at room temperature for about <NUM> hours to prepare each sustained-release lipid pre-concentrate. The total batch size thereof was prepared in <NUM> per pre-concentrate.

Sustained-release injectable pharmaceutical compositions in the form of a lipid solution containing leuprolide acetate were prepared according to the components and amounts shown in Table <NUM>. The amounts of Table <NUM> represent the weight percent (wt%) of each component in the pharmaceutical composition. Specifically, phosphatidylcholine, oleic acid, DL-α-tocopherol acetate, medium chain triglyceride [Kollisolv™ MCT <NUM> (a mixture of tricapryline and tricaprine, about <NUM>:<NUM> of weight ratio), BASF], and/or an aqueous solution of ethanol (ethanol : water for injection = <NUM> : <NUM>) were added to a glass vial; and then mixed under stirring at room temperature with a magnetic stirrer. Each resulting mixture was homogenized at room temperature with a homogenizer (POLYTRON PT1200E, KINEMATICA) under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes. Leuprolide acetate was added to each mixture, which was homogenized at room temperature with a homogenizer under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes and then left at room temperature for about <NUM> hours to prepare the sustained-release injectable pharmaceutical compositions in the form of a lipid solution.

Sustained-release injectable pharmaceutical compositions in the form of a lipid solution containing goserelin acetate were prepared according to the components and amounts shown in Table <NUM>. The amounts of Table <NUM> represent the weight percent (wt%) of each component in the pharmaceutical composition. Specifically, phosphatidylcholine, oleic acid, DL-α-tocopherol acetate, medium chain triglyceride [Kollisolv™ MCT <NUM> (a mixture of tricapryline and tricaprine, about <NUM>:<NUM> of weight ratio), BASF], and/or an aqueous solution of ethanol (ethanol : water for injection = <NUM> : <NUM> or <NUM> : <NUM>) were added to a glass vial; and then mixed under stirring at room temperature with a magnetic stirrer. Each resulting mixture was homogenized at room temperature with a homogenizer (POLYTRON PT1200E, KINEMATICA) under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes. Goserelin acetate was added to each mixture, which was homogenized at room temperature with a homogenizer under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes and then left at room temperature for about <NUM> hours to prepare the sustained-release injectable pharmaceutical compositions in the form of a lipid solution.

Sustained-release injectable pharmaceutical compositions in the form of a lipid solution containing liraglutide were prepared according to the components and amounts shown in Table <NUM>. The amounts of Table <NUM> represent the weight percent (wt%) of each component in the pharmaceutical composition. Specifically, phosphatidylcholine, oleic acid, DL-α-tocopherol acetate, medium chain triglyceride [Kollisolv™ MCT <NUM> (a mixture of tricapryline and tricaprine, about <NUM>:<NUM> of weight ratio), BASF], and/or an aqueous solution of ethanol (ethanol : water for injection = <NUM> : <NUM>) were added to a glass vial; and then mixed under stirring at room temperature with a magnetic stirrer. Each resulting mixture was homogenized at room temperature with a homogenizer (POLYTRON PT1200E, KINEMATICA) under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes. Liraglutide was added to each mixture, which was homogenized at room temperature with a homogenizer under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes and then left at room temperature for about <NUM> hours to prepare the sustained-release injectable pharmaceutical compositions in the form of a lipid solution.

Sustained-release injectable pharmaceutical compositions in the form of a lipid solution containing dutasteride were prepared according to the components and amounts shown in Table <NUM>. The amounts of Table <NUM> represent the weight percent (wt%) of each component in the pharmaceutical composition. Specifically, phosphatidylcholine, oleic acid, DL-α-tocopherol acetate, medium chain triglyceride [Kollisolv™ MCT <NUM> (a mixture of tricapryline and tricaprine, about <NUM>:<NUM> of weight ratio), BASF], and/or ethanol were added to a glass vial; and then mixed under stirring at room temperature with a magnetic stirrer. Each resulting mixture was homogenized at room temperature with a homogenizer (POLYTRON PT1200E, KINEMATICA) under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes. Dutasteride was added to each mixture, which was homogenized at room temperature with a homogenizer under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes and then left at room temperature for about <NUM> hours to prepare the sustained-release injectable pharmaceutical compositions in the form of a lipid solution.

Sustained-release injectable pharmaceutical compositions in the form of a lipid solution containing paliperidone were prepared according to the components and amounts shown in Table <NUM>. The amounts of Table <NUM> represent the weight percent (wt%) of each component in the pharmaceutical composition. Specifically, phosphatidylcholine, oleic acid, DL-α-tocopherol acetate, medium chain triglyceride [Kollisolv™ MCT <NUM> (a mixture of tricapryline and tricaprine, about <NUM>:<NUM> of weight ratio), BASF], ethanol and benzyl alcohol were added to a glass vial; and then mixed under stirring at room temperature with a magnetic stirrer. Each resulting mixture was homogenized at room temperature with a homogenizer (POLYTRON PT1200E, KINEMATICA) under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes. Paliperidone was added to each mixture, which was homogenized at room temperature with a homogenizer under the condition of about <NUM>,<NUM> rpm for about <NUM> minutes and then left at room temperature for about <NUM> hours to prepare the sustained-release injectable pharmaceutical compositions in the form of a lipid solution.

Sustained-release lipid pre-concentrates were prepared according to the components and amounts shown in Tables <NUM> and <NUM>. The amounts of Tables <NUM> and <NUM> represent the weight percent (wt%) of each component in the sustained-release lipid pre-concentrate. The sustained-release lipid pre-concentrates of Comparative Examples <NUM> to <NUM> were prepared in the same manner as in Examples <NUM> to <NUM>, using glyceryl dioleate instead of oleic acid, according to the components and amounts of Table <NUM>. And, the sustained-release lipid pre-concentrates of Comparative Examples <NUM> to <NUM> were prepared in the same manner as in Examples <NUM> to <NUM>, using sorbitan monooleate instead of oleic acid, according to the components and amounts of Table <NUM>.

In order to evaluate the injectability of the sustained-release lipid pre-concentrates prepared in Examples <NUM> to <NUM> and Comparative Examples <NUM> to <NUM>, the viscosity of each sustained-release lipid pre-concentrate was measured using a cone-plate rotating viscometer (RM-<NUM> touch, Ramy). The results of Examples <NUM> and <NUM> and Comparative Examples <NUM>, <NUM>, <NUM> and <NUM> are shown in <FIG>. As can be seen from the above results, the sustained-release lipid pre-concentrate containing sorbitan monooleate showed about <NUM>~<NUM> times higher viscosities, in comparison with the sustained-release pre-concentrate containing oleic acid or glyceryl dioleate, and thus exhibited remarkably low injectability. In addition, the sustained-release lipid pre-concentrates containing oleic acid showed lower viscosities under the same condition, in comparison with the sustained-release lipid pre-concentrates containing glyceryl dioleate, and thus exhibited the most excellent injectability.

The sustained-release lipid pre-concentrates prepared in Examples <NUM>, <NUM>, <NUM> and <NUM> and Comparative Examples <NUM> to <NUM> were filled in a <NUM> syringe and injected into <NUM> of pH <NUM> phosphate buffer through a <NUM> gauge needle. The resulting appearances thereof are shown in <FIG>. As can be seen from the results of <FIG>, all of the sustained-release lipid pre-concentrates were in the form of a fluidal lipid solution at room temperature before exposure to the aqueous phase; and formed a liquid crystal matrix when injected into the aqueous phase. However, in contrast to the sustained-release lipid pre-concentrates containing glyceryl dioleate (the pre-concentrates of Comparative Examples <NUM> to <NUM>), the sustained-release lipid pre-concentrates containing oleic acid (the pre-concentrates of Examples <NUM>, <NUM>, <NUM> and <NUM>) and the sustained-release lipid pre-concentrates containing sorbitan monooleate (the pre-concentrates of Comparative Examples <NUM> to <NUM>) formed an ideal spherical liquid crystal matrix, thereby exhibiting excellent matrix (liquid crystal)-forming ability.

<NUM>µl of the sustained-release lipid pre-concentrate prepared in Example <NUM> was thinly applied to a slide glass, and then placed in a petri dish containing <NUM> of pH <NUM> phosphate buffer and left at room temperature for about <NUM> hours. In order to confirm the liquid crystal structure formed by exposure to the aqueous phase, the water on the slide glass was carefully removed and a cover glass was covered so that no air bubbles were generated, and then it was observed at <NUM> magnification using a polarizing microscope (S38, MIC). The result thereof is shown in <FIG>. From the result of <FIG>, it can be confirmed that the sustained-release lipid pre-concentrate prepared according to the present invention forms a reversed hexagonal phase that enables sustained release of the pharmacologically active substance upon exposure to an aqueous phase.

The sustained-release injectable pharmaceutical compositions in the form of a lipid solution prepared in Examples <NUM> to <NUM> were filled in a <NUM> syringe, and then <NUM> thereof was respectively injected into a glass vial containing <NUM> of pH <NUM> phosphate buffer through a <NUM> gauge needle, so as to form a matrix. Each glass vial was stored in an oven maintained at <NUM>. The matrix in the vial was carefully taken out at each measuring time, the moisture on the surface was eliminated, and then the viscosity of the matrix was measured using a cone-plate rotating viscometer (RM-<NUM> touch, Ramy). The results thereof are shown in <FIG>. From the results of <FIG>, the viscosity of the matrix increased rapidly within <NUM> minutes (<NUM> hours), which indicates that the pharmaceutical compositions obtained according to the present invention form a robust matrix capable of maintaining its shape even despite external forces within <NUM> minutes, when they are exposed to an aqueous phase. Therefore, when the sustained-release injectable pharmaceutical compositions in the form of a lipid solution obtained according to the present invention is injected into a living body, a matrix is also rapidly formed, thereby effectively avoiding the initial burst release of a pharmacologically active substance.

Sustained-release effects were confirmed by performing in vitro release tests on the sustained-release injectable pharmaceutical compositions in the form of a lipid solution prepared in Examples <NUM> and <NUM>. Specifically, a sample container capable of loading the pharmaceutical composition was prepared by attaching <NUM> mesh and <NUM> mesh sieves to both sides of an acrylic tube (inner diameter: <NUM>, height: <NUM>). And, a pH <NUM> test solution containing <NUM> of polysorbate <NUM>, <NUM> of triethylamine, and <NUM> of phosphoric acid was prepared. The sample container loaded with <NUM> of each sustained-release injectable pharmaceutical composition in the form of a lipid solution and the test solution were placed in a <NUM> test container (outer diameter: <NUM>, height: <NUM>), which was mounted on a water bath-bottle rotating apparatus (BDSHWB-980R, Bandi Tech). While the apparatus was stirred at <NUM> at <NUM> rpm, the samples were taken for <NUM> days and then analyzed by HPLC under the following conditions.

The results obtained by performing the in vitro release tests as described above are shown in <FIG>. From the results of <FIG>, it can be confirmed that the sustained-release injectable pharmaceutical compositions in the form of a lipid solution obtained according to the present invention exhibit an effective sustained-release pattern for a long period of time.

Sustained-release effect was confirmed by performing in vitro release test on the sustained-release injectable pharmaceutical composition in the form of a lipid solution prepared in Example <NUM>. Specifically, a sample container capable of loading the sustained-release lipid solution was prepared by attaching <NUM> mesh and <NUM> mesh sieves to both sides of an acrylic tube (inner diameter: <NUM>, height: <NUM>). And, a pH <NUM> phosphate buffer containing <NUM> of polysorbate <NUM> was prepared as a test solution. The sample container loaded with <NUM> of the sustained-release injectable pharmaceutical composition in the form of a lipid solution and the test solution were placed in a <NUM> test container (outer diameter: <NUM>, height: <NUM>), which was mounted on a water bath-bottle rotating apparatus (BDSHWB-980R, Bandi Tech). While the apparatus was stirred at <NUM> at <NUM> rpm, the samples were taken for <NUM> days and then analyzed by HPLC under the following conditions.

Claim 1:
A sustained-release lipid pre-concentrate in the form of a lipid solution, comprising an unsaturated fatty acid having <NUM> to <NUM> carbon atoms (C<NUM>~C<NUM>); a phospholipid; and α-tocopherol acetate, wherein the sustained-release lipid pre-concentrate is free of diacyl glycerol and sorbitan unsaturated fatty acid ester; and forms a liquid crystal in an aqueous medium.