JP5515075B2 - Fine particle formulation - Google Patents

Description

The present invention relates to a fine particle formulation comprising fine particles that can contain a drug that is an active ingredient as nano-level fine particles, a method for stabilizing fine particles, and the like.

  The microparticle preparation of the present invention is useful as, for example, a drug for intravenous injection.

  As a conventional technique, for example, Non-Patent Document 1 below discloses liposome microparticles prepared using amphotericin B (hereinafter referred to as “AMPH-B”), which is an antifungal agent, and a phospholipid derivative of polyethylene glycol in the presence of serum components. Attempts to stabilize with are described.

K. Moribe, E .; Tanaka, K .; Maruyama and M.M. Iwatsuru, Enhanced encapsulation of amphotericin B into liposomes by complex formation with polyethyl derivatives. Pharm. Res. 15, 1737-1742 (1998).

  Micellar microparticles made of phospholipid derivatives of AMPH-B and polyethylene glycol can also be applied as a microparticle formulation, but have the disadvantage of poor stability in water and aggregation immediately.

  Then, in view of the said subject, this invention aims at providing the fine particle formulation which can make a chemical | medical agent exist as a micelle type microparticle more stably, the stabilization method of a microparticle, or a microparticle formulation.

  As a result of diligent studies on the above problems, the present inventors have discovered that stable fine particles can be obtained by adding an ascorbic acid derivative to a surfactant and a drug such as a phospholipid derivative, and the present invention has been completed. I came to let you.

  That is, as one means for solving the above-described problems, the present invention provides a fine particle preparation containing an ascorbic acid derivative, a surfactant, and a drug.

  Furthermore, the present invention relates to a method for stabilizing the fine particles or the fine particle preparation, further comprising adding an ascorbic acid derivative to fine particles comprising a surfactant or a fine particle preparation containing the drug in the fine particles.

  ADVANTAGE OF THE INVENTION According to this invention, the microparticle formulation which can make a chemical | medical agent exist as a microparticle more stably can be provided. In the present fine particle preparation, the drug is stably present as fine particles in a solvent, and can exhibit extremely excellent efficacy as a drug. Further, since the present fine particle preparation is considered to be a micelle-type nano fine particle having a water-soluble polymer such as polyethylene glycol on its surface, it can be expected to exist stably in blood for a long time. Since the drug is present inside the fine particles, an effect of reducing side effects due to the drug is also expected.

It is a figure which shows the result of the UPA measurement with respect to the samples 1 thru | or 3. It is a figure which shows the result of the confirmation experiment about the stability of the microparticles | fine-particles with respect to the samples 1 thru | or 4. FIG. 6 is a diagram showing the result of UPA measurement for sample 4. It is a figure which shows the result of the confirmation experiment about the stability in the biological component of the microparticles | fine-particles with respect to the samples 2 and 4. FIG. Fine particles are prepared by mixing L-ascorbic acid 2,6-dipalmitate (ASC-DP) in various molar ratios with distearoylphosphatidylethanolamine polyethylene glycol 2000 (DSPE-PEG2000) as a phospholipid derivative, It is a figure which shows the result of the UPA measurement with respect to. In the figure, (a) DSPE-PEG single micelle, (b) ASC-DP: DSPE-PEG (0.5: 1), (c) ASC-DP: DSPE-PEG (2: 1), (d) ASC-DP : DSPE-PEG (2.1: 1). The result of having measured the state of the particle | grains of the fine particle formulation of this invention which enclosed amphotericin B by atomic force microscope (AFM) is shown. Particles having a size of about 60-80 nm and a height of about 5 nm were confirmed.

Hereinafter, embodiments of the present invention will be described in detail. However, it should be understood that the present invention can be implemented in many different forms and is not limited to the embodiments and examples described below. Absent.

  One feature of the fine particle formulation according to the present invention is that it contains an ascorbic acid derivative, a surfactant, and a drug. The fine particle formulation according to the present invention can exist as micelle-like nano fine particles which are stable in a solvent when used by containing them. As a result, it can be expected to exist stably in blood for a long time, and since the drug is present inside the fine particles, an effect of reducing side effects due to the drug can be expected.

  Here, the “ascorbic acid derivative” refers to a compound obtained by converting a part of the molecular structure of ascorbic acid using ascorbic acid as a starting material. In addition, although it does not necessarily limit about the ascorbic acid derivative which concerns on this invention, For example, it is preferable that it is what is shown by following formula (1).

(In the above formula, R ₁ and R ₂ are acyl chains which may have a side chain having 8 to 20 carbon atoms. R ₁ and R ₂ may be the same or different. )

  Specific examples of the ascorbic acid derivative represented by the above formula (1) include L-ascorbic acid 2,6-dipalmitate (ASC-DP) represented by the following formula (3), L-ascorbic acid 2,6-dibutyrate ( ASC-DB), L-ascorbic acid 6-monopalmitate (ASC-P), and L-ascorbic acid 6-monostearate (ASC-S). Among these, ASC-DP is particularly preferable in terms of stabilization of the fine particle preparation.

The content of the ascorbic acid derivative in the microparticles or microparticle preparation according to the present invention is not limited, but preferably 3 mol or less, more preferably 1 mol or more and 2 mol or less, relative to 1 mol of the surfactant. It is.

Here, the “surfactant” refers to any substance known to those skilled in the art. For example, as a representative example of the surfactant, various phospholipid derivatives and cholesterol derivatives described in Examples in the present specification can be mentioned.

Here, as described above, the “phospholipid derivative” refers to a compound obtained by converting a part of the molecular structure of a polar group that binds to a phosphate group using diacylglycerol phosphate as a starting material. The “cholesterol derivative” refers to a compound obtained by converting a part of the molecular structure of the polar group of cholesterol into a group such as polyethylene glycol. Although it does not necessarily limit as an example of a phospholipid derivative, It is preferable that it is a compound shown by following formula (2).

(In the above formula, R ₁ and R ₂ are alkyl chains which may have a side chain having 8 to 20 carbon atoms. R ₁ and R ₂ may be the same or different. R ₃ is a polyethylene glycol, polypropylene glycol or polyglycerin chain and is bonded to the phosphate group directly or via a spacer, and the spacer in the above formula is any group known to those skilled in the art. For example, it may be a group having a structure such as —CH ₂ CH ₂ NHCO— and —CH ₂ CH ₂ NHCO—CH ₂ CH ₂ CO—, and the molecular weight of polyethylene glycol contained in the derivative is arbitrary, A range of 1000 to 5000 is preferred.)

Furthermore, as specific examples of the phospholipid derivative, distearoylphosphatidylethanolamine polyethylene glycol (DSPE-PEG) represented by the following formula (4), and as specific examples of the cholesterol derivative, CHOL-PEG1000 and CHOL -Cholesterol-PEG (CHOL-PEG) represented by PEG2000 and the like can be mentioned.

The drug according to the present invention is not limited, but includes antifungal drugs, diabetes drugs, anticancer drugs, antiepileptic drugs, hypnotics, diuretics, antipyretic analgesics, antirheumatic drugs, vitamins, etc. It is preferable to contain at least one of these.

  In the case of an antifungal agent, examples include, but are not limited to, amphotericin B (hereinafter referred to as “AMPH-B”), nystatin, pimaricin and the like. Amphotericin B exerts antibacterial activity by damaging the plasma membrane of sensitive cells due to its amphipathicity, more specifically, specific interaction with sterols, particularly ergosterol, abundantly contained in cell membranes It is suitable for the treatment of deep fungus because the membrane permeability is changed by

  Moreover, although it is not necessarily limited, in the case of an antidiabetic drug, for example, glibenclamide and gliculaside can be mentioned.

  Moreover, although not necessarily limited, in the case of an anticancer drug, a spicamycin can be mentioned, for example.

  Moreover, although not necessarily limited, in the case of an antiepileptic drug, for example, phenytoin can be mentioned.

    Moreover, although not necessarily limited, in the case of a hypnotic, for example, nitrazepam can be mentioned.

    Moreover, although not necessarily limited, in the case of a diuretic, spironolactone can be mentioned, for example.

  Further, the content of the drug in the fine particle preparation according to the present invention is not limited, but it is contained within a range of 0.1 mol or more and 0.2 mol or less with respect to 1 mol of the surfactant used. Is preferred.

  In addition, the ascorbic acid derivative, the surfactant, and the drug contained in the present fine particle formulation may each be one kind or a mixture of several kinds.

  In addition to the above-mentioned components, the fine particle formulation according to the present invention may appropriately contain known components that are acceptable as a formulation. Although not necessarily limited, for example, at least one of a stabilizer, a pH adjuster, and a disaccharide can be appropriately contained.

  The fine particle formulation according to the present invention can be produced by any method known to those skilled in the art.

  For example, the fine particle preparation according to the present invention is prepared by adding ascorbic acid, a phospholipid derivative, and a drug to an organic solvent and stirring, then evaporating the solvent, re-dissolving in a solvent such as water, and then performing ultrasonic treatment and the like. It can be obtained by applying. In addition, this fine particle formulation can be administered by injection after evaporating a solvent such as water during storage, and again dissolving and dispersing in the solvent during use. The organic solvent is not limited as long as an ascorbic acid derivative, a surfactant and a drug can be added and stirred to form micelles. For example, organic solvents such as chloroform, methanol, and diethyl ether can be used. Mention may be made of solvents. In addition, it is also a preferable aspect that the ascorbic acid derivative, the surfactant, and the drug are dissolved in separate organic solvents and then mixed. As a result, the particle size of the fine particle formulation according to the present invention is usually in the range of about 40 to 300 nm.

  The administration route of the microparticle preparation according to the present invention is not particularly limited, but it is a preferred embodiment that, when used, it is dissolved and dispersed in a solvent and administered by injection. The solvent used in this use is not limited as long as micelles can be formed, but water is preferable from the viewpoint of safety to the human body. The fine particle preparation according to the present invention can be appropriately prepared depending on the age, weight, sex, and medical condition of the administration subject, and is not particularly limited.

  As described above, according to the present invention, it is possible to provide a fine particle formulation in which a drug is present more stably as fine particles.

  Hereinafter, the fine particle formulation of the present invention was actually produced and the effect was confirmed. In the following examples, L-ascorbic acid 2,6-dipalmitate (hereinafter referred to as “ASC-DP”) is used as the ascorbic acid derivative, and distearoylphosphatidylethanolamine polyethylene glycol (DSPE-PEG) is used as the phospholipid derivative. (Specifically, “DSPE-PEG2000”) will be described using an example in which AMPH-B is used as a drug, wherein ASC-DP used in this example is represented by the following formula (3), and DSPE-PEG is represented by the following formula. In (4), AMPH-B is shown in the following formula (5).

(In the above formula, n is an integer of 20 to 120, preferably 40 to 50.)

  First, ASC-DP and DSPE-PEG were dissolved in chloroform (4 ml) to obtain a substantially transparent solution. On the other hand, AMPH-B was dissolved in methanol, and this methanol solution was mixed with the chloroform solution in which the above ASC-DP and DSPE-PEG were dissolved. And this mixed solution was evaporated, drawing a vacuum at 60 degreeC, and the yellow thin film was obtained.

  Next, the thin film obtained as a result of this evaporation was dissolved in a 9% sucrose aqueous solution and dispersed using ultrasonic waves for 3 minutes to obtain each sample solution (sample numbers 1 to 3). In this example, the fine particles and their stability were also evaluated by changing the amounts of ASC-DP, DSPE-PEG and AMPH-B. The amounts of ASC-DP, DSPE-PEG, and AMPH-B and their ratios are shown in Table 1 below.

  FIG. 1 shows the results of microtrack particle size distribution measurement (MICROTRAC Ultrafine Particle Analyzer, manufactured by Nikkiso Co., Ltd.) (hereinafter referred to as “UPA measurement”) performed on samples 1 to 3 immediately after preparation (FIG. 1 (a). ) Shows sample 1, (b) shows sample 2, and (c) shows sample 3)). As a result, in each of the sample solutions, it was confirmed that the particle diameter was in the range of 120 nm to 250 nm, and it was confirmed that the particles were sufficiently small.

  Next, the stability of the fine particles in each sample was confirmed. This confirmation was performed by placing each sample container in a dark room at 25 ° C. to shield it from light, and measuring the change in the particle diameter over time (the particle diameter was measured by the UPA measurement). The result is shown in FIG. As a result, it was confirmed that Samples 1 to 3 existed stably for 7 days or more without large particle size fluctuations. On the other hand, in the sample 4 solution to which ASC-DP was not added, the particle diameter was about 5 nm immediately after preparation, but it increased rapidly to 129 nm after 1 day and 2157 nm after 7 days. (See FIGS. 2 and 3. FIG. 3 is a diagram showing the results of UPA measurement on sample 4. FIG. 3 (a) is immediately after preparation, (b) is one day later, (c) is 7 days later). In Sample 4, AMPH-B crystals were also precipitated 7 days after preparation.

  Furthermore, the stability of each sample in the biological components was also confirmed. This confirmation was performed by adding a serum component (PBS solution containing 10% FBS) to Sample 2 or Sample 4, shielding the light, and incubating in a 37 ° C. water bath, and measuring the change in particle diameter over time. The result is shown in FIG. As a result, it was confirmed that the sample 2 was stably present for 15 hours or more, and was confirmed to be sufficiently stable even in the biological component. As a result, it was confirmed that it was stably held in the solution, and the effect of the present invention was confirmed. In Sample 4, it became a large mass of several hundred μm to several mm in less than 30 minutes after the start of measurement, and it was still lacking in stability.

Furthermore, microparticles were prepared by mixing L-ascorbic acid 2,6-dipalmitate (ASC-DP) in various molar ratios with distearoylphosphatidylethanolamine polyethylene glycol 2000 (DSPE-PEG2000), a phospholipid derivative. And their stability was evaluated.

Samples were prepared by weighing ASC-DP and DSPE-PEG2000 in molar ratios of 0.5: 1, 1: 1, 2.0: 1, 2.1: 1, 2.3: 1, 2.5: 1, 3.0: 1 and then placed in an eggplant flask. Was dissolved in chloroform, and the solvent was distilled off with a rotary evaporator. The obtained thin film was hydrated with purified water, subjected to ultrasonic generation treatment (Sonics Vibra Cell VC130, SONICS & MATERIAL, Inc.), and was dispersed uniformly in water, and UPA measurement was performed. Table 2 shows the stability results based on the obtained particle size distribution values.

The particle size of the micelle of DSPE-PEG2000 alone is about 4-10 nm. The particle diameter of the fine particles prepared using ASC-DP and DSPE-PEG2000 in various molar ratios increases as the amount of ASC-DP added increases. As a result, it was found that when the molar ratio of the two was in the range of 1: 1 to 2: 1, the fine particles existed as nanoparticles having an average particle diameter of 100 nm or less. On the other hand, when the molar ratio was 3: 1, the average particle diameter was 521 nm, and the presence of several μm particles was observed. Furthermore, there were particles that were clearly observable with eyes at a molar ratio of 4: 1. Considering that the measurable range of the microtrack particle size distribution measurement is 7 μm at the maximum, it was considered that 4: 1 is a region in which the particle diameter evaluation is difficult and there are almost no particles that can be regarded as nano-fine particles. Therefore, when the molar ratio was 2: 1 or more, the average particle diameter rapidly increased to 400 nm or more, and there were particles of several μm, so it was considered that nanoparticle formation would be difficult. On the other hand, when the addition ratio of ASC-DP to DSPE-PEG is small, such as the molar ratio of 0.5: 1 or less, the distribution of DSPE-PEG micelles in addition to the nanoparticle size distribution Appeared. The above results are shown in FIG. From the above results, it was speculated that the molar ratio suitable for ASC-DP to stabilize DSPE-PEG2000 was 3: 1 or less, particularly preferably in the range of 1: 1 to 2: 1.

  Further, the above microparticles were dispersed in water, and after 24 hours, the microtrack particle size distribution was measured in the same manner. As a result, the particle diameter of the fine particles having the molar ratio of 1: 1 was changed from 78 nm to 71 nm, and the particle diameter of the fine particles having the molar ratio of 0.5: 1 was changed from 44 nm to 38 nm. Considering that there is a distribution, it can be considered that these particle diameters hardly change or slightly decrease.

Fine particles were produced using DSPE-PEG2000 and various ascorbic acid derivatives, and their stability was evaluated. As an ascorbic acid derivative, L-ascorbic acid 2,6-dipalmitate (ASC-DP), L-ascorbic acid 2,6-dibutyrate (ASC-DB), L-ascorbic acid 6-monopalmitate (ASC-P), L-ascorbic acid 6-monostearate (ASC-S) and distearoylphosphatidylethanolamine polyethylene glycol 2000 (DSPE-PEG2000) were used as a phospholipid derivative.

The sample was prepared by weighing an ascorbic acid derivative and DSPE-PEG2000 at a molar ratio of 1: 1, placing them in an eggplant flask, dissolving in chloroform, and removing the solvent with a rotary evaporator. The obtained thin film was hydrated with purified water, subjected to ultrasonic generation treatment (Sonics Vibra Cell VC130, SONICS & MATERIAL, Inc.), and UPA measurement was performed on the thin film uniformly dispersed in water. Table 3 shows the stability results based on the obtained particle size distribution values.

As a result, when ASC-DP was used, stable nano-particles of about 100 nm were formed by dispersing in water, and the particle size was almost the same even after storage for 1 week. When ASC-P and ASC-S were used, they were solubilized in DSPE-PEG2000 after being dispersed in water, and the solution was almost transparent. However, a gradual increase in particle diameter was observed over time, and the presence of particles of 1 μm or more was confirmed after 1 day. Even when ASC-DB was used, solubilization in DSPE-PEG2000 was observed and the same state was maintained even after 1 day, but the presence of particles of 1 μm or more was confirmed after 3 days. From the above results, it was found that ASC-DP is most useful for stabilizing DSPE-PEG2000 micelles.

Fine particles were produced using ascorbic acid derivatives (ASC-DP) and various surfactants, and their stability was evaluated. As a surfactant, distearoylphosphatidylethanolamine polyethylene glycol 2000 (DSPE-PEG2000), distearoylphosphatidylethanolamine polyethylene glycol 5000 (DSPE-PEG5000), distearoylglycerol 2000, cholesterol-PEG1000 (CHOL-PEG1000), Cholesterol-PEG2000 (CHOL-PEG2000), Lauromacrogol, Cetyltrimethylammonium bromide (CTAB), Sodium lauryl sulfate (SDS), Diacylglycerol 5000, Polyvinyl alcohol (PVA), Polyethylene glycol 6000 (PEG6000), Decaethylene glycol mono Dodecyl ether (Brij 78) was used.

The sample was prepared by weighing ASC-DP and a surfactant at a molar ratio of 1: 1, placing them in an eggplant flask, dissolving them in chloroform, and distilling off the solvent with a rotary evaporator. The obtained thin film was hydrated with purified water, subjected to ultrasonic generation treatment (Sonics Vibra Cell VC130, SONICS & MATERIAL, Inc.), and UPA measurement was performed on the thin film uniformly dispersed in water. Table 4 shows the stability results based on the obtained particle size distribution values.

As a result, when DSPE-PEG2000 was used, stable nano-particles of about 100 nm were formed by dispersing in water, and the particle diameter was almost the same even after storage for 1 week. Even when DSPE-PEG5000 was used, nanoparticles were observed after dispersion in water, and the same state was maintained even after one day. However, when the storage time was further extended, an increase in the particle size was observed, and a precipitate was confirmed after 7 days. When diacylglycerol 2000 was used, micro-sized fine particles were observed after dispersion in water, and the same state was maintained even after 1 day, but a precipitate was confirmed after 7 days. When CHOLO-PEG1000 and CHOL-PEG2000 Lauromacrogol were used, nanoparticles were observed after dispersion in water. However, a gradual increase in particle diameter was observed over time, and the presence of particles of 1 μm or more was confirmed after 1 day, and precipitates were observed after storage for 1 week. When CTAB and SDS were used, microparticles were observed after dispersion in water. However, a gradual increase in particle size was observed over time, and a precipitate was observed after 1 day. When diacylglycerol 5000, PVA, PEG6000, or Brij78 was used, the presence of fine particles was not observed after dispersion in water, and precipitation was observed. From the above results, it was found that the micelle stabilization effect by ASC-DP is most useful in DSPE-PEG2000 micelles.

The fine particle formulation of the present invention in which a drug was encapsulated was produced and its stability was evaluated. That is, ascorbic acid derivative (ASC-DP), phospholipid derivative (DSPE-PEG2000), and amphotericin B, clarithromycin, fluconazole, acetohexamide, nystatin, nitrazepam, phenytoin, piroxicam, spironolactone, ibuprofen, glimepiride Vitamin A palmitate, α-tocopherol, α-lipoic acid, vitamin K, vitamin D, and CoQ10 were used.

Samples were prepared as ternary samples, ASC-DP, DSPE-PEG2000, drug in molar ratio 1: 1: 0.1, and as binary samples, DSPE-PEG2000, encapsulated drug in molar ratio 1: 0.1. Was dissolved in chloroform, and the solvent was distilled off with a rotary evaporator. The obtained thin film was hydrated with purified water, subjected to ultrasonic generation treatment (Sonics Vibra Cell VC130, SONICS & MATERIAL, Inc.), and UPA measurement was performed on the thin film uniformly dispersed in water. The stability results are shown in Table 5 based on the obtained particle size distribution values.

As a result, when amphotericin B, clarithromycin, fluconazole, and acetohexamide are encapsulated, three-component samples disperse in water to form stable nano-particles of about 100 nm and maintain the same particle size even after one day. Was. FIG. 6 shows the result of atomic force microscope (AFM) measurement of the state of the fine particle preparation containing amphotericin B. On the other hand, in the two-component sample, aggregation was observed immediately after preparation. When nystatin was encapsulated, stable nano-particles of about 100 nm were formed by dispersing in water in the three-component sample, and the same particle size was maintained even after one day. On the other hand, in the two-component sample, although nanoparticles of about 100 nm were formed immediately after preparation, the presence of particles of 1 μm or more was confirmed one day later. When nitrazepam and phenytoin were encapsulated, in the three-component sample, stable nanoparticles having a size of about 100 nm were formed by dispersing in water, and the same particle size was maintained even after one day. In the two-component sample, nanoparticles of about 100 nm were formed. When piroxicam was encapsulated, stable nano-particles of about 100 nm were formed in the three-component sample by dispersing in water. However, a gradual increase in particle diameter was observed over time, and the presence of particles of 1 μm or more was confirmed after 1 day. When spironolactone, ibuprofen, and glimepiride were encapsulated, formation of fine particles was not observed in the three-component sample and the two-component sample.
From the above results, it was found that DSPE-PEG2000 micelles stabilized by ASC-DP can stably encapsulate poorly water-soluble drugs such as amphotericin B and can stabilize a fine particle formulation containing them.

Microparticles were prepared by adding 0.1 in a molar ratio of amphotericin B to DSPE-PEG2000, and a toxicity test was performed. Fungizone of amphotericin B solubilized with sodium deoxycholate, amphotericin B / DSPE-PEG2000 = 0.1 / 1mol / mol, amphotericin B / DSPE-PEG2000 / ASC-DP = 0.1 / 1 / 1mol / mol in mice Microvenous administration was performed. Administration was converted to the amount of amphotericin B per mouse body weight and increased to 1 mg, 2 mg, 4 mg, 6 mg, and thereafter 2 mg each, and each was administered to 3 mice. The concentration at which all mice die after administration was defined as the maximum tolerated dose (MTD). As a result of the toxicity test of various microparticle preparations shown in Table 6, it was found that the toxicity of amphotericin B / DSPE-PEG2000 / ASC-DP microparticles was clearly reduced as compared with the commercial microparticle preparation Fungizone.

  The present invention can be applied as a stable fine particle preparation, for example, as an intravenous injection, and has industrial applicability.

Claims (10)

A micelle type fine particle having a particle diameter of 40 to 300 nm, comprising an ascorbic acid derivative represented by the following general formula (1), a surfactant containing a phospholipid derivative represented by the following general formula (2) , and a drug. Fine particle preparation formed.
(In the above formula, R ₁ and R ₂ are acyl chains having 8 to 20 carbon atoms which may have a side chain . R ₁ and R ₂ may be the same or different. )
(In the above formula, R ₁ and R ₂ are alkyl chains having 8 to 20 carbon atoms which may have a side chain. R ₁ and R ₂ may be the same or different. R ₃ contains either polyethylene glycol, polypropylene glycol, or polyglycerin chain, and is bonded to the phosphate group directly or via a spacer.   The fine particle formulation according to claim 1, wherein the ascorbic acid derivative comprises L-ascorbic acid 2,6-dipalmitate. The phospholipid derivative comprises a phospholipid derivative of the following formula (3), microparticle preparation according to claim 1, wherein the.
(In the above formula, n is an integer of 20 to 120.)   2. The drug according to claim 1, wherein the drug includes at least one of antifungal drugs, diabetes drugs, anticancer drugs, antiepileptic drugs, hypnotics, diuretics, antipyretic analgesics, antirheumatic drugs, and vitamins. Fine particle formulation. The microparticle formulation of claim 4 , wherein the antifungal agent comprises amphotericin B.   The fine particle formulation according to claim 1, wherein the ascorbic acid derivative is contained in an amount of 1 mol to 2 mol with respect to 1 mol of the surfactant. A fine particle comprising a surfactant containing a phospholipid derivative represented by the following general formula (2) or a fine particle preparation containing a drug in the fine particle, and further containing an ascorbic acid derivative represented by the following general formula (1) A method for stabilizing the fine particles or the fine particle preparation, wherein micelle-type fine particles having a diameter of 40 to 300 nm are formed.
(In the above formula, R ₁ and R ₂ are acyl chains having 8 to 20 carbon atoms which may have a side chain . R ₁ and R ₂ may be the same or different. )
(In the above formula, R ₁ and R ₂ are alkyl chains having 8 to 20 carbon atoms which may have a side chain. R ₁ and R ₂ may be the same or different. R ₃ contains either polyethylene glycol, polypropylene glycol, or polyglycerin chain, and is bonded to the phosphate group directly or via a spacer. The stabilization method of Claim 7 in which the said surfactant contains the phospholipid derivative shown by following formula (3).
(In the above formula, n is an integer of 20 to 120.) The stabilization method according to claim 7 , wherein the ascorbic acid derivative is contained in an amount of 1 mol to 2 mol with respect to 1 mol of the surfactant. The stabilization method according to claim 7 , wherein the ascorbic acid derivative contains L-ascorbic acid 2,6-dipalmitate, and the surfactant contains a phospholipid derivative represented by the following formula (3).
(In the above formula, n is an integer of 20 to 120.)