JPS63215642A - Pharmaceutical composition containing natural albumin as carrier and production thereof - Google Patents

Abstract

PURPOSE:To obtain the titled composition having mitigated side effects, improved absorbability of drug component and improved light stability, by suspending natural albumin in an aqueous solution, adding a drug exhibiting protein-bonding action to the suspension, stirring the mixture at a high speed and removing the solvent. CONSTITUTION:A natural albumin (preferably ovalbumin) is suspended in an aqueous solution (preferably water) to obtain a suspension having a concentration of 2-25wt.%. A drug exhibiting protein-bonding property (e.g. nalidixic acid) is dissolved in an organic solvent having a boiling point of <=100 deg.C (e.g. acetone), added to the suspension and agitated at 4-30 deg.C at a high speed (5,000-40,000rpm) for 1-30hr to obtain a homogeneous layer. The organic solvent is removed from the layer by distillation under reduced pressure and the residue is dried to obtain a pharmaceutical composition composed of 1-200pts. of the drug component and 100pts. of natural albumin. The composition can reduce the injury on especially digestive system and increase the content of the drug component.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a pharmaceutical composition using albumin as a carrier, which contains one or more pharmaceuticals having an affinity for albumin at a high concentration by the method described below. More specifically, the present invention relates to a pharmaceutical composition that reduces undesirable side effects on the human body, improves absorption of pharmaceuticals, and improves photostability.

[Prior art and its problems]

Conventionally, as a pharmaceutical composition using albumin as a carrier, 5-
Complex of fluorouracil derivative and albumin (JP-A-54-151988), sustained-release albumin complex (
JP-A No. 58-162595). However, the method described in this patent publication has a pH of 6 to 1.
), at a temperature of 30°C or lower, it is necessary to change the binding properties of the carrier albumin in advance using cyanogen halide or perhalogenated acid, and it is also necessary to add a spacer such as a functional compound to improve the affinity for eyebrows. do.

On the other hand, the pharmaceutical composition of the present invention using natural albumin as a carrier does not require cyanogen halides, perhalogen acids, or spacers, as described below, and is completely different from those described in the previous patent publications. Other examples include cyclodextrin-indomethacin inclusion complexes using cyclodextrin (JP-A-54-62313, JP-A-54-1
) No. 7018), and products containing indomethacin in a biodegradable carrier selected from collagen, gelatin, etc. (Japanese Patent Application Laid-open No. 84213/1983), but these conventional products are slow-release. However, it is poorly absorbed in the body and takes a long time to develop its medicinal effects.

An object of the present invention is to provide a pharmaceutical composition that can reduce the damage caused by pharmaceuticals to the skin and mucous membranes, particularly the digestive system, and improve the absorbability, stability to light, etc. of pharmaceuticals.

[Means for solving problems]

The present invention has been made to achieve the above-mentioned object, and the pharmaceutical composition of the present invention is characterized by comprising 1 to 200 parts of a pharmaceutical exhibiting protein-binding properties and 100 parts of natural albumin.

Incidentally, JP-A-58-216126 describes the use of human serum albumin to make water-insoluble or poorly soluble drugs soluble. However, the method described in this patent publication is an application of the conventionally known method for measuring the protein binding rate of pharmaceuticals, and even pharmaceuticals that can be solubilized have a ratio of 0.01 to 0.8 with respect to serum albumin. %, and it is an exceptionally useful technique only when the clinical dose is extremely low, as in the case of prostaglandin shown in this patent publication.

On the other hand, in the pharmaceutical composition of the present invention using natural albumin as a carrier, as described in detail below, the albumin used in the present invention includes, for example, ovalbumin, serum albumin, plaque albumin, α-lactalbumin,
Examples include leucosin, phaselin, and levumelin, and ovalbumin is particularly preferred. Also,
In order to apply the composition obtained according to the present invention to the field of pharmaceuticals where antigenicity is a problem, it is preferable to use human-derived albumin. It is suitable that the drug used in the present invention has a protein binding rate of 10% or more, preferably 20% or more. In addition, the blending amount is at least 1 part, preferably 5 to 20 parts, per 100 parts of albumin.
Preferably, it is used in a proportion of 0 parts.

In addition, specific examples of pharmaceuticals used in the present invention include:
Antipyretic, analgesic and anti-inflammatory agents such as aspirin, ibuprofen, alclofenac, indomethacin, mefenamic acid, flufenamic acid, sulindac, piroxicam, diclofenac sodium, tialamide, tolmetin; steroidal anti-inflammatory agents such as prednisolone, triamcinolone, dexamethacin, Beclomethasone, hydrocortisone, etc.; as neuropsychiatric agents, chlorpromazine hydrochloride, carbamazepine, clonazepam, phenytoin, haloperidol, chlordiazepoxide, mexazolam, amitributyline hydrochloride, imipramine hydrochloride, flunitrazepam, triazolam, etc.; as antihypertensive diuretics, furosemide, ethacrynic acid, bumetanide, hydrochlorothiazide , trichloromethiazide, metolazone, chlorthalidone, etc.; hypertensive drugs such as prazosin hydrochloride, reserpine, lapeclol, clonidine hydrochloride, bunazosin hydrochloride, captopril, hydralazine hydrochloride, budralazine, etc.; cardiovascular agents such as theophylline, etilefrine hydrochloride, hydrochloric acid Dobutamine, quinidine sulfate, lidocaine, mexiletine hydrochloride, digitoxin, digoxin, deslanoside, vinpocetine, cinepamide maleate, etc.; as coronary vasodilators, diltiazem hydrochloride, nifedipine, verapamil hydrochloride, nicardipine hydrochloride, isosorbide nitrate, nitroglycerin, etc.; sympathetic nerve effects Medications such as isoprenaline hydrochloride; peripheral skeletal muscle relaxants such as eperisone hydrochloride, dantrolene, and batalofen; therapeutic drugs for ischemic heart disease such as dilazep hydrochloride, dibilitamol, and nicorandil; beta-agonist agents such as etilefrine hydrochloride, Doptamine hydrochloride, etc.; as a β-blocker,
Alprenol hydrochloride, propranolol hydrochloride, ofsprerol hydrochloride, pindolol, etc.; antispasmodics such as athrobin, scobramin; antibiotics cef1chlor, cephalexin, floxacin, vibesidic acid, sulfamethoxacecefazolin sodium, cefmetuxime hydrochloride , Cefoxitin Sodium, Cefoxitin Sodium, Latamoxef Sodium, Ampicillin, Sulpenicillin Sodium, Benzylpenicillin Power 1.1
Antifungal agents include griseofulvin, nyscutin, amphotericin B1 miconazole, etc.; Therapeutic agents include nalidixic acid, enoxacin, and ozole; antiviral agents include vidarabine; anti-malignant agents include methotrexate, vindesine sulfate, vincristine sulfate, and daunorubicin hydrochloride; therapeutic agents for peptic ulcers include cetraxate hydrochloride, cimetidine, Famotidine, pirenzepine hydrochloride, ranitidine hydrochloride, sulpiride, etc.; as anti-allergic agents, such as tetrafen, tranilast, azelastine, chlorpheniramine maleate, lemastine fumarate, mequitazine, etc.; as an expectorant, amproxal hydrochloride, etc.; as vitamins , cardiotriol,
Tocopherol acetate, tocopherol nicotinate, riboflavin, folic acid, menadione, phytonadione, etc.; Malotylate, glycyrrhizin, etc. for use in liver diseases;
Antidiabetic agents such as acetohexamide, chlorpropamide, tolbutamide; Hormonal agents such as danazol, levothyroxine, liothyronine, propylthiouracil; Uric acid excretion agents such as probenecid; Immunosuppressants such as azathioprine and cyclosporine;
Antiemetics include tonbelitone and the like.

The method for producing the pharmaceutical-albumin composition of the present invention will be specifically explained using an example of a nalidixic acid-albumin composition.

First, natural albumin such as ovalbumin is suspended in an aqueous solution, and a suitable solution having a boiling point of 100°C or less is added to the suspension.
1 Add nalidixic acid dissolved in a solvent and stir at high speed to form a uniform layer. The temperature at this time is not particularly limited as long as the albumin is not denatured, but is preferably 4 to 4.
It is necessary to stir at high speed for about 1 to 30 hours at a temperature of 30°C.
Approx.
It is preferable to carry out under the condition of 00Qrpm. The concentration of the albumin suspension during the production of this composition is not particularly limited, but at least Iff! L% can be used preferably at a concentration of 2 to 25% by weight. The ratio of albumin to nalidixic acid is generally 100% albumin
It is preferable to use 5 to 100 parts of nalidixic acid per part of nalidixic acid. Any aqueous solution can be used as long as it dissolves albumin without denaturing it, but water is most preferred. However, a portion of the water can also be replaced with a water-soluble solvent such as methanol, ethanol, impropatol, acetone, etc. Furthermore, examples of the organic solvent used when dissolving nalidixic acid in an organic solvent include acetone, chloroform, methanol, ethanol, and the like. The concentration of nalidixic acid in the solution is not particularly limited, but it is advantageous to dissolve it in a concentration of at least 0.1% by weight, preferably in the range of 1 to 50% by weight. In addition, the mixing ratio of the nalidixic acid solution dissolved in an organic solvent and the albumin suspension is not particularly limited, but preferably 1 volume of the nalidixic acid solution to 100 volumes of the albumin suspension.
Mix in a range of ~400 volumes. The organic solvent used is distilled off from the reaction solution thus obtained at a temperature of 40° C. or lower under reduced pressure. Thereafter, the desired powdered nalidixic acid-albumin composition can be obtained by removing the aqueous solvent using means such as spray drying or freeze drying. The composition obtained here reacts almost 100% regardless of the ratio of both nalidixic acid and albumin, and depending on the ratio of both added, the ratio of nalidixic acid to albumin is about 5 to 100%.
A 100% bound composition is obtained.

Although an example of manufacturing a nalidixic acid-albumin composition has been described above, a pharmaceutical-albumin composition in which other pharmaceuticals are supported on albumin can also be manufactured in a similar manner. In addition to the nalidixic acid-albumin composition, in the production of the pharmaceutical-albumin composition of the present invention, fatty oil and/or fatty acid can be used together with the pharmaceutical and albumin, and the resulting pharmaceutical-albumin composition The absorbency of objects is further improved.

The following experiment proves that the nalidixic acid-albumin composition obtained above improves the absorption of nalidixic acid taken after meals.

Lysix Bis1 Zix - Albuminarisix
Experimental animals containing 8.9% I" were used: male Wistar rats (weight 290 g, Sankyo Lab) under satiated conditions.

Administration and blood collection The dose was 50 mg/day as nalidixic acid.
kg. The drug was administered in a suspended state in 1 ml of water using an oral gastric tube. Capillary (Drummon d.

Approximately 0.2 ml of blood was collected from the fundus at 0.1 ml).
Serum was obtained by centrifugation.

Sample processing and serum was mixed with an equal volume of methanol to remove protein.

Quantification using high performance liquid chromatography It was done by law.

Quantification conditions Column: TOYO3ODA.

ODS-807M.

4.6mmX 15cm Mobile phase niacetonitrile: 5 0mM citric acid solution :IM ammonium acetate Ram-35:64: Flow rate: 0.7ml/min Detection wavelength: 258nm Injection tube: 10μl Column temperature: room temperature The calibration curve uses blank serum. Adding the known nalidixic acid, I decided to process it in the same way as the sample. Obtained from

Results The results are shown in Figure 1.

As is clear from Figure 1, when the nalidixic acid-albumin composition was administered at 50 mg/kg as nalidixic acid, the maximum blood concentration was reached within 1.5 hours after administration, and the concentration at this time was approximately 25 μg. /m1. On the other hand, when administering the same amount of nalidixic acid bulk powder,
The maximum blood concentration is reached within a certain period of time, and the concentration at this time is approximately 7μ.
It was estimated that g. In addition, when calculating the lower surface i (AUG) of the 0-8 hour serum concentration curve for both, the composition was 108.9 μg-hr/ml, and the bulk powder was 34.6 μg.
-hr/ml. From the comparison of these pharmacodynamic parameters, it can be determined that the absorbability of the composition of the present invention is superior to that of the bulk powder. Generally, pharmaceutical compositions in which a drug is adsorbed or bound to a carrier are released in a sustained manner and absorption is delayed, but it can be seen from FIG. 1 that absorption is accelerated in the composition of the present invention compared to the bulk powder.

Next, an example in which the side effects on the gastrointestinal tract of the present invention are reduced will be explained. Although non-steroidal anti-inflammatory drugs have a strong anti-inflammatory effect on inflamed areas, they are known to cause bleeding and ulcers in the digestive system. The indomethacin-albumin composition produced by the above-described method exhibits an anti-inflammatory effect equivalent to that of indomethacin, which is a non-steroidal anti-inflammatory agent, without causing ulcer formation. This is proven by the following experiment.

Test method The test was performed using the method of Sekibe et al. [Japanese Journal of Pharmacology (J, J ap.

Pharmacol, ) 29S670 pages (1979)]
I followed the instructions.

That is, Wistar weighing 180 to 200 g.
After fasting rats (8 rats per group) for about 18 hours, an indomethacin-albumin composition was added as a sample to 20 mg of indomethacin at 1% to give 7 kg.
Karpodiki methyl cellulose sodium solution (1% CM
(abbreviated as CNa) per 100g of rat.
．． It was orally administered at a rate of 5 ml. In addition, as a control, indomethacin bulk powder was added at 1% to 20 mg/kg.
A suspension in CM CN a was administered in the same manner.

Seven hours after administration, all rats were sacrificed with ether and 8 ml of a 1% buffered formalin aqueous solution was injected into the stomach, which was then removed and 1% buffered formalin was removed.
The stomach was immersed in a buffered formalin aqueous solution for 15 minutes. Next, the stomach was incised along the greater curvature and the gastric mucosa was observed under a stereomicroscope. If a damaged area (ulcer) was found, its major axis (mm
) was measured. The sum was taken as the ulcer incidence coefficient, and 39 mm or more was defined as +, 10 to 30 mm was 2, 5 to 1Q mm was +, and below that, no ulcer occurrence was observed.

The results are shown in Table 1.

As is clear from Table 1, 7 hours after administration,
Ulcers were observed on the gold side in the indomethacin bulk powder administration group, but up to 6 out of 8 subjects in the indomethacin-albumin composition administration group did not observe ulcer formation, and only a small number of ulcers were observed.
In this case, the ulcer was also small.

Furthermore, the anti-inflammatory effect of the indomethacin-albumin composition is demonstrated by the following experiment.

Indomethacin-albumin; Judgment was made by the carrageenin foot edema method.

That is, Wistar weighing 150 to 180 g.
r) After fasting for about 18 hours using male rats (5 rats per group), the volume of the rat hind limb edema was measured using a rat hind paw edema volume measuring device (Natsume Seisakusho, T
K-101 type) was used to determine the pre-administration value. As a sample, the indomethacin-albumin composition was mixed at 1% to give about 5 mg/kg of indomethacin.
A suspension in CM CN a and a similar suspension of indomethacin bulk powder at a concentration of 5 mg/kg were orally administered at a rate of 0.5 ml per 100 g of rats. As a control, 1% CMCNa was orally administered at a rate of Q, 5 ml (7) per 100 g of rats. 30 minutes after oral administration, 0.1 ml of 1% λ-carrageenan saline solution was subcutaneously administered to the right hind foot of the rat.
Immediately thereafter, 5 ml of water was orally administered. Foot edema was measured 3 hours after administration of 1% λ-carrageenan. The following formulas (1), (2
), the inhibition rate of carrageenan foot edema was determined.

×100 The results are shown in Table 2.

As is clear from Table 2, the indomethacin-albumin composition exhibits approximately the same effect as the bulk indomethacin powder and exhibits excellent anti-inflammatory action.

Next, examples of improved photostability according to the present invention will be shown. The following experiment proves that the nifedipine-albumin composition prepared by the above method has excellent stability against light.

Nifedipine-albumin, 0.1 g of nifedipine-albumin composition containing about 0.01 g of fresh formula 4 nifedipine and about 0.0 g of nifedipine as a control.
．． 1 g and 0.1 g of commercially available nifedipine fine granules containing about 0°001 g of nifedipine were placed in a flat plate as shown in Figure 2 (
50 x 50 cm) and spread it out into a 2 x 2 cm square at 10 cm intervals.

This flat plate was covered with a wooden box, and an attached fluorescent lamp (10 W manufactured by Toshiba) was turned on in the center of the flat plate and left for 24 hours. The room temperature at the start of the experiment was 12°C and relative humidity 30%, and at the end the room temperature was 12°C.
The temperature was 9°C and relative humidity 25%.

After irradiation with light, each sample was collected spot by spot, weighed accurately, and mixed with IQml of methanol, and washed in an ultrasonic cleaner (high frequency output 150W, 28kHz) for 3 hours.
Ultrasonic waves were applied for 0 minutes. Insoluble matter was filtered off, the remaining amount on the funnel was washed with methanol, the filtrate and washing liquid were combined, and the total volume was made up to 150 ml with methanol to provide a sample solution. Approximately 100 mg each of the nifedipine-albumin composition, nifedipine bulk powder, and commercially available nifedipine fine granules, which had been stored in the same manner under light protection, were accurately weighed, and 19 ml of methanol was added thereto, followed by the same procedure to obtain a control solution. However, for the nifedipine bulk powder, both the control solution and the sample solution were further accurately diluted to 10 times the volume. A fixed amount of both the control solution and the sample solution was accurately injected into a high-performance liquid chromatography system to quantify the concentration of nifedipine. The quantitative determination was calculated from a calibration curve obtained by simultaneously analyzing two different nifedipine standard solutions with known concentrations. The analysis conditions for high performance liquid chromatography are as follows.

Column: Waters type, Tsubapack 018 moving bed:
55% methanol flow rate: l m I/min detection wavelength: 3
The 50 nm residual rate was calculated using the following formula.

The results are shown in Table 3.

Sample residual rate (average) Nifedipine bulk powder 30.2 (Same as above) Commercially available Nifedipine fine granules 40.6 (Same as above) As is clear from Table 3, the nifedipine-albumin composition does not inhibit the photodegradation of the nifedipine it contains. and the degree of stability was superior to that of commercially available nifedipine fine granules. Furthermore, this stability is improved by common formulation processing.

Furthermore, fat-soluble vitamin ッ-α, which is one of the compositions of the present invention
The following experiments demonstrate that the -tocopherol-ovalbumin composition is superior in absorption properties.

Tocopherol-white albumin combination J -α-tocopherol alone and a-α-tocopherol-ovalbumin composition (dl-α).

- an amount equivalent to 100 mg as tocopherol) was filled into two No. OO capsules and orally administered to dogs. Blood was collected from the limb vein at 3.6.9.12.24.36 hours after oral administration, and serum was obtained after centrifugation. 1 ml of methanol and 5 ml of hexane were added to 0.5 ml of serum, and the mixture was shaken for 10 minutes. After 5 ml of hexane phase was evaporated to dryness, 300 μl of hexane was added, and 25 μl of the mixture was used as a high performance liquid chromatography sample.

Conditions for high performance liquid chromatography: Lichrosorb 5I-60 (74
m, 4mm, j, d, x 25cm) Mobile phase: hexane:isopropanol (99,5:0
．． 5) Flow rate = 1.0 ml/min Detection wavelength: Excitation wavelength 295 nm Fluorescence wavelength 330 nm The results are as shown in Figure 4, R-α-tocopherol-
When the ovalbumin composition was administered, an increase in the serum concentration of -α-tocopherol was observed. The area under the serum concentration one-hour curve (AUC) is ovalbumin: 8-α-
Tocopherol: stearic acid (5:1:0.5)
2.8 times that of single administration, ovalbumin: dl-
In the case of α-tocopherol (5:1), it increased 1.6 times. In particular, when stearic acid was added, the time to reach the maximum blood concentration was shortened from 12 hours when administered alone to 6 hours. These results indicate that the -α-tocopherol-ovalbumin composition has extremely excellent absorption properties.

Thus, when the composition of the present invention is used as a drug, it can be manufactured into a variety of forms for oral administration. It can be formulated as a drug containing together with a carrier material that is acceptable to the manufacturer. Depending on the intended use, such drugs may be in solid form (e.g., tablets, capsules, granules, powders, granules, dragees, lozenges, etc.) or semi-solid forms (e.g., ointments, poultices, creams, suppositories). ) and liquid form! 3 (e.g., emulsions, suspensions, liquids, tinctures, sprays, syrups, etc.).Therefore, non-toxic, pharmaceutically acceptable formulations that can be used may be prepared. Examples of the carrier material to be obtained include starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, polyalkylene glycol,
Examples include p-hydroxybenzoic acid alkyl ester, simple syrup, ethanol, propylene glycol, glycerin, vaseline, carbowax and the like. The agent may also contain other therapeutically useful agents, dispersants, antioxidants, preservatives, stabilizers, flavoring agents, binders, blanching agents, and the like.

The content of the composition of the invention in the medicament varies depending on its form, but generally at a concentration of 5 to 100% by weight for solid and semi-solid forms and 0.1% for liquid forms. It is desirable to contain the active compound in a concentration of ~10% by weight.

Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1 Add 18 g of ovalbumin to 400 ml of distilled water and use a biolyzer (Model BM-4 manufactured by Nippon Seiki Seisakusho) while cooling.
A homogeneous phase was obtained by stirring at a high speed of about 1)000 Orp using a . 2 g of nifedipine in 6 ml of acetone
and added to the homogeneous phase. High-speed stirring was continued for 1 hour while further cooling, and the organic solvent was distilled off under reduced pressure from the resulting homogeneous suspension, followed by freeze-drying to obtain a powder. This powder was passed through a 100 mesh sieve to obtain a nifedipine-albumin composition with uniform particle size. The obtained nifedibine-albumin composition had a plate-like three-dimensional structure with a longest particle diameter of 15 μm, as shown in the scanning electron micrograph of FIG.

Examples 2 to 22 Example 1 except that the pharmaceuticals and solvents shown in Table 4 were used, and the high-speed stirring conditions and drying conditions were appropriately varied according to the types, physical properties, etc. of the pharmaceuticals and solvents used. Powders of various pharmaceutical-albumin compositions were obtained in the same manner as above.

Table 4 Pharmaceuticals and solvents and their usage amounts 2 Aspirin 2 Ethanol 203 Indometase
2 Ethanol 204 Nalidixic acid 2 Chloroform 605 Piroxicam 2 Acetone 8
06 Sulindac 2 Methanol 100 Table 4 continued 8 Cefaclor 2 Distilled water 1009 Cefalexi 2 Distilled water 100 12 Dexamethazo 1 Ethanol 100 14 Haloberide-2 Methanol 100 16 Cephalexi 1 Distilled water 100 20 Ketotifen 2 Methanol 8021 Glycyrrhizi 2 methanol 60 N22 Tranilast 2 Acetone 200*8-α
-Tocopherol-ovalbumin composition (1:5
) except one f1') 7j! An a-α-tocopherol-ovalbumin-stearic acid composition (1:5:0.5·) was also prepared using 1.8 g.

〔Effect of the invention〕

The pharmaceutical composition of the present invention using natural albumin as a carrier has remarkable effects such as reducing unfavorable side effects on the human body, improving absorption of pharmaceuticals, and having excellent photostability.

[Brief explanation of the drawing]

Figure 1 is a graph showing changes in blood concentration over time after administration of the nalidixic acid-alpmin composition, and Figure 2 is a graph showing changes in blood concentration over time after administration of nalidixic acid-alpmin composition.
Figure 4 shows the flat plate used to arrange various samples in the photostability test of albumin compositions, etc. The vJs diagram is a scanning electron micrograph of the nifedipine-albumin composition, and Figure 4 shows the α-tocopherol albumin. 6 is a graph showing changes over time in blood concentration after administration of an albumin composition. Applicant Japan Highbox Co., Ltd. Agent Patent attorney Shizuka Nakamura Man A: Nifedipine-albumin composition B: Nifedipine bulk powder C: Nifedipine Chia A grains D: Albumin Drawing engraving time (hr) Procedural amendment writing method) % formula % 1. Indication of the incident Patent Application No. 49135 of 1988 2. Name of the invention Pharmaceutical composition using natural albumin as a carrier and its manufacturing method Name Nihon Hibox Yanumavir Co., Ltd. No. 802 May 26, 1988 7 , Details of the amendment (1) "Scanning electron micrograph" on page 29, line 18 of the specification is corrected to scanning electron micrograph 1 showing the WJ structure of r crystal. (2) Replace the drawings with the attached corrected drawings (Figures 2 and 4).

Claims (2)

[Claims] (1) A pharmaceutical composition comprising 1 to 200 parts of a pharmaceutical exhibiting protein-binding properties and 100 parts of natural albumin. (2) A method for producing a pharmaceutical composition, which comprises suspending natural albumin in an aqueous solution, adding 1 to 200 parts of the drug to 100 parts of natural albumin, stirring at high speed, and then removing the solvent.