The present invention relates to an anhydrous liquid composition wherein monoglyceride is mixed with an emulsifier and a solvent, and the manufacturing method thereof, and more specifically, to an anhydrous liquid composition wherein monoglyceride is mixed with a water-insoluble material, an emulsifier and a solvent, and the manufacturing method thereof. Further, the present invention relates to a lyophilized powder and the manufacturing method thereof, wherein the lyophilized powder is prepared by dissolving the mixed liquid composition in water, adding with a cryoprotectant followed by the lyophilization. In the process of dispersion, the lyophilized liquid composition and the powder of the present invention can spontaneously generate particles of 200-500 nm by gently shaking with hands without a powerful mechanical force. Also the lyophilized liquid composition and the powder of the present invention are physicochemically stable since they neither contain water that causes oxidation or hydrolysis upon storage nor undergo phase separation. Considering all the raw materials of the present invention are biocompatible, the present invention will be useful in medical and pharmaceutical fields such as drug delivery.

SUMMARY OF THE INVENTION

After intensive studies to solve the above problems, the inventors of the present invention finally succeeded in preparing a homogeneous liquid formulation comprising monoglycerides, emulsifiers and organic solvents. This liquid formulation can be easily dispersed in water, without using a harsh physical force, to form a dispersion of particles of less than 500 nm. The homogeneous liquid formulation is physically stable since it is a single phase liquid, and also chemically stable since it does not contain water and does not require physical force during the formulation process. The liquid formulation of the present invention, therefore, can be stored for a prolonged period of time.

Therefore, the object of the present invention is to provide a novel solubilizing composition, which enables stable solubilization of materials as well as stable long-term storage, and the manufacturing method thereof.

Another object of the present invention is to provide a liquid formulation and a powder formulation for said solubilizing composition, and the manufacturing method thereof.

Still another object of the present invention is to provide a liquid formulation and a powder formulation for said solubilizing composition to be used in drug delivery system wherein pharmaceutical compounds are added, and the manufacturing method thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a solubilizing composition comprising 9˜90% by weight of at least one monoglyceride, 0.01˜90% by weight of at least one emulsifier, and 0˜90.9% by weight of an organic solvent. The above composition is prepared by dissolving at least one monoglyceride compound and an emulsifier in an organic solvent followed by removing the organic solvent.

The monoglyceride compound is preferred to select at least one from saturated or unsaturated C₁₀-C₂₂ monoglycerides. The monoglyceride compound used in the present invention is monoolein, monopalmitolein, monomyristolein, monoeladin, and monoerucin, and more preferably monoolein.

The emulsifier is preferred to select from the group consisting of phospholipid, a non-ionic surfactant, an anionic surfactant, a cationic surfactant, and bile acid.

The phospholipid is preferred to select from the group consisting of a phosphatidylcholine (PC) and its derivative, a phosphatidylethanolamine (PE) and its derivative, a phosphatidylserine (PS) and its derivative or a polymeric lipid wherein a hydrophilic polymer is conjugated to the lipid headgroup.

The non-ionic surfactant is selected from the group consisting of a poloxamer (also known as Pluronic: polyoxyethylene-polyoxypropylene copolymer), a sorbitan ester (Span), a polyoxyethylene sorbitan (Tween) or a polyoxyethylene ether (Brij).

The anionic surfactant is selected from the group consisting of a phosphatidylserine (PS) and its derivative, a phosphatidic acid (PA) and its derivative or sodium dodecyl sulfate (SDS).

The cationic surfactant is selected from the group consisting of 1,2-dioleyl-3-trimethylammonium propane (DOTAP), dimethyldioctadecylammonium bromide (DDAB), N-[1-(1,2-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), 1,2-dioleyl-3-ethylphosphocholine (DOEPC) or 3β-[N-[(N′,N′-dimethylamino)ethan]carbamoyl]cholesterol (DC-Chol).

The bile acid is selected from the group consisting of cholic acid, its salt and derivatives; deoxycholic acid, its salt and derivatives; chenocholic acid, its salt and derivatives; ursodeoxycholic acid, its salt and derivatives; and lithocholic acid, its salt and derivatives.

The organic solvent is preferred to select from the group consisting of alcohol, ethylene glycol, propylene glycol, polyethylene glycol (PEG), dimethylsulfoxide (DMSO) or the mixture of these solvents. The organic solvents such as acetone, chloroform, benzene, toluene, acetonitrile, alcohols or the mixture of these solvents, which dissolve both a lipid emulsifier and a water-insoluble compound, can also be used.

Other additives can be added to the above composition to be within 5% by weight and the Examples are fatty acids, fatty acid esters and fatty acid alcohols.

The present invention relates to a liquid formulation of the above solubilizing composition.

The liquid formulation of the present invention comprises 9˜90% by weight of at least one monoglyceride, 0.01˜90% by weight of at least one emulsifier, and 9˜90.9% by weight of an organic solvent. The above liquid formulation is manufactured by mixing 1˜99% by weight of the above solubilizing composition with 1˜99% by weight of an organic solvent. More specifically, the method of manufacturing the above liquid formulation comprises (a) completely dissolving at least one monoglyceride compound and at least one emulsifier in an organic solvent and removing the organic solvent; and (b) preparing a homogeneous liquid phase by mixing the composition in the above step (a) with an organic solvent.

In the above step (a), an organic solvent is preferred to select from the group consisting of alcohol, chloroform, benzene, toluene, acetonitrile or the mixture of these solvents, and more preferably ethanol.

In the above step (b), an organic solvent is preferred to select from the group consisting of alcohol, ethylene glycol, propylene glycol, polyethylene glycol (PEG), dimethylsulfoxide (DMSO) or the mixture of these solvents. The organic solvents such as acetone, chloroform, benzene, toluene, acetonitrile, alcohols or the mixture of these solvents, which dissolve both a lipid emulsifier and a water-insoluble compound, can also be used.

An Example of manufacturing the above liquid formulation is as follows. First, one or more monoglycerides and one or more emulsifiers are completely dissolved in an organic solvent such as ethanol, and then the solvent is evaporated either by heating at about 40° C. under a nitrogen atmosphere or by applying a low atmospheric pressure. Here, a trace amount of ethanol that may be still present in the mixture does not affect the property of the final formulation. To this viscous liquid, i.e., the solubilizing composition, a solvent such as ethanol, propylene glycol, ethylene glycol, polyethylene glycol, dimethylsulfoxide (DMSO), is added to prepare a homogeneous mixed liquid formulation.

The present invention relates to manufacturing of a powder formulation by lyophilizing the dispersion of the above liquid formulation.

The above powder formulation is manufactured by dissolving the above liquid formulation, which comprises 9˜90% by weight of at least one monoglyceride compound, 0.01˜90% by weight of at least one emulsifier, and 9˜90.9% by weight of an organic solvent, in excess water followed by lyophilization. More specifically, the method of manufacturing the above powder formulation comprises the steps of (a) dispersing the liquid formulation in excess water; and lyophilizing said dispersed liquid in step (b) by selectively adding a cryoprotectant.

A cryoprotectant may be used to prevent the morphological changes of the particles in the dispersion of the above formulation during lyophilization, and it is preferred to add it less than 30% (w/v) to the liquid formulation. Preferred Examples of a cryoprotectant include sugars such as mannitol or trehalose, amino acids such as arginine, and proteins such as albumin.

The present invention relates to the utilization of the solubilizing liquid formulation in the drug delivery system for water-insoluble or amphiphilic compounds. In particular, the present invention relates to solubilizing liquid formulations and powder formulations, and the manufacturing method thereof.

The solubilizing liquid formulation comprises 9˜90% by weight of at least one monoglyceride compound, 0.01˜90% by weight of at least one emulsifier, 0.001˜50% by weight of a pharmaceutical compound and 9˜90.9% by weight of an organic solvent.

The kinds of monoglyceride compound, an emulsifier and an organic solvent are the same as described above.

The above solubilizing formulations can enclose a hydrophilic, a hydrophobic and an amphiphilic compound as a pharmaceutical compound. Examples of these pharmaceutical compounds that can be used in the present invention are antivirals, steroidal anti-inflammatory drugs (SAID), non-steroidal anti-inflammatory drugs (NSAID), antibiotics, antifungals, vitamins, hormones, retinoic acid, prostaglandins, prostacyclins, anticancer drugs, antimetabolitic drugs, miotics, cholinergics, adrenergic antagonists, anticonvulsants, antianxiety agents, major tranquilizers, antidepressants, anesthetics, analgesics, anabolic steroids, estrogens, progesterones, glycosaminoglycans, polynucleotides, immunosuppressants and immunostimulants. In particular, pharmaceutical compounds such as cyclosporin A and paclitaxel, an immunosuppressant and an anticancer drug, which are generally hard to be solubilized can be readily solubilized in the present invention.

The solubilizing liquid formulations containing the above-mentioned pharmaceutical compounds can enclose 5% by weight or less of other conventional additives including fatty acids and ester derivatives thereof and alcohol derivatives thereof.

The method of manufacturing solubilizing liquid formulations containing the above-mentioned pharmaceutical compounds comprises (a) dissolving at least one monoglyceride compound, at least one pharmaceutical compound and at least one emulsifier in an organic solvent and removing the organic solvent; and (b) preparing a homogeneous liquid phase by mixing the composition in the above step (a) with an organic solvent.

In the above step (a), the preferred organic solvents are alcohol, chloroform, benzene, toluene, acetonitrile or the mixture of these solvents, and more preferably ethanol.

In the above step (b), the preferred organic solvents are alcohol, ethyleneglycol, propylene glycol, polyethyleneglycol, dimethylsulfoxide (DMSO) or the mixture of these solvents. The organic solvents such as acetone, chloroform, benzene, toluene, acetonitrile, alcohols or the mixture of these solvents, which dissolve both a lipid emulsifier and a water-insoluble compound, can also be used.

An Example of manufacturing the above liquid formulation is as follows. First, a monoglyceride compound and an emulsifier are completely dissolved in a solvent such as ethanol and then the solvent is evaporated either by heating at about 40° C. under a nitrogen atmosphere or by applying low atmospheric pressure. Here, a trace amount of ethanol that may be still present in the mixture does not affect the property of the final formulation. To this viscous liquid, in other words, the solubilizing composition, is added with an equal amount of solvent such as ethanol, ethylene glycol, propylene glycol, polyethylene glycol, dimethylsulfoxide (DMSO), and a homogeneous mixed liquid formulation is finally prepared.

The present invention is related to manufacturing of a water-insoluble solubilizing powder formulation containing a pharmaceutical compound by lyophilization of the dispersion prepared with the above solubilizing liquid formulation containing water-insoluble materials.

The above powder formulation comprises. The method of manufacturing the above powder formulation comprises the steps of (a) dispersing the liquid formulation comprising 9˜90% by weight of at least one monoglyceride compound, 0.01˜90% by weight of at least one emulsifier, 0.001˜50% by weight of a pharmaceutical compound and 9˜90.9% by weight of an organic solvent in excess water; and lyophilizing said dispersed liquid in step (b) by selectively adding a cryoprotectant.

A cryoprotectant may be used to prevent the morphological changes in the dispersion of the above formulation during lyophilization, and it is preferred to add it less than 30% (w/v) to the liquid formulation. Preferred Examples of a cryoprotectant include sugars such as mannitol or trehalose, amino acids such as arginine, and proteins such as albumin.

The above formulation of the present invention can be easily dispersed in water mediated by such a minimal mechanical aid as a simply shaking with hands. The size of particles is approximately 200˜500 nm in general and varies depending on the property of a given pharmaceutical compounds or an emulsifier. Moreover, the constituting ingredients of and pharmaceutical compound in the particles are not degraded since a strong mechanical force is not required in generating the particles.

The formulations according to the present invention can be stored at room temperature in a sealed state for a long period of time without undergoing phase separation or the change in properties of the formulations. When a long-term storage is required, the powder formulation is desirable because it does not contact with an organic solvent or moisture.

The formulations according to the present invention are useful in drug delivery system because they exhibit a sustained drug release pattern. When applying these formulations in drug delivery system, it is preferred to use various administration routes including intravenous injection, mucosal administration, buccal administration and nasal administration, and more preferably an oral administration.
 

Claim 1 of 30 Claims

1. A solubilizing composition comprising 9˜90% by weight of at least one monoglyceride compound, 0.01˜90% by weight of at least one emulsifier, 0˜50% by weight of at least one water-insoluble material, 0˜90.9% by weight of organic solvent and 0˜5% by weight of other additives;

wherein the solubilizing composition comprises cubosome particles.

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