JPS63215640A - Easily absorbable anti-inflammatory agent and production thereof - Google Patents

Abstract

PURPOSE:To obtain an easily absorbable anti-inflammatory agent causing reduced gastrointestinal injury, by agitating a non-steroidal anti-inflammatory agent and natural albumin in a specific aqueous medium at a high speed and distilling out the aqueous solvent. CONSTITUTION:The titled agent composed of a composition comprising (A) a non-steroidal anti-inflammatory agent (e.g. indomethacin, piroxicam and acetylsalicylic acid) and (B) a natural albumin (preferably ovalbumin) can be produced either by contacting the component A with the component B in an aqueous solvent under agitation at a high speed and distilling out the aqueous solvent or by dissolving the component A in a fatty oil (e.g. olive oil) and/or a fatty acid (e.g. 8-30C straight-chain fatty acid), adding the solution to an aqueous suspension of natural albumin, agitating the mixture at a high speed and distilling out the aqueous solvent. The ratio of the component A to B is 5-100:100 and the agitation is carried out preferably at room temperature at a rotational speed of 5,000-30,000rpm for 1-30hr.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an easily absorbable anti-inflammatory agent with reduced gastrointestinal disorders, which is composed of a non-steroidal anti-inflammatory agent and albumin.

[Prior art and its problems]

While non-steroidal anti-inflammatory drugs have a strong anti-inflammatory effect on inflamed areas, they are known to cause serious side effects on the central and digestive systems, and are known to cause bleeding and ulcers, especially in the digestive system. ing. Various pharmaceutical compositions have been researched and reported to alleviate such side effects. for example,
0.2 to 50 per part by weight of the non-steroidal anti-inflammatory drug or its salt! A pharmaceutical composition in which indomethacin is combined with a certain amount of salicylic acid or an alkali salicylate as an activating agent is known (Japanese Patent Application Laid-Open No. 82715/1982). (Japanese Patent Application Laid-Open No. 60-8421)
3), it has been disclosed that sustained release can be achieved by forming an inclusion complex of indomethacin and cyclodextrin (JP-A-54-62313, JP-A-54
-117018). Furthermore, JP-A-54-1103
Publication No. 34 discloses a method of combining indomethacin and a benzodiazepine compound to reduce the dosage and prevent the occurrence of serious side effects.

Although these conventional methods have excellent sustained release properties, they are poorly absorbed into the body, require a long time to produce anti-inflammatory effects, and are not sufficiently effective to eliminate side effects on the digestive system. There are very few that are effective.

Therefore, an object of the present invention is to provide a non-steroidal anti-inflammatory agent that causes less gastrointestinal disorder and has excellent absorbability.

[Means for solving problems]

The present invention has been made to achieve the above object, and the easily absorbable anti-inflammatory agent with reduced gastrointestinal disorders of the present invention comprises a composition of a non-steroidal anti-inflammatory agent and natural albumin. Features.

Note that Japanese Patent Application Laid-Open No. 58-216126 describes the use of human serum albumin to solubilize water-insoluble or poorly soluble drugs. However, the method described in this patent publication is an application of the conventionally known method for measuring the binding rate of Kumbaku for pharmaceuticals, and the solubilized pharmaceuticals also have a ratio of 0.01 to 0.8 with respect to serum albumin. %
It is a technique that is exceptionally useful only at very low clinical doses, as in the case of the prostaglandins shown in this patent publication.

On the other hand, the non-steroidal anti-inflammatory agent-natural albumin composition of the present invention is completely different from those described in the previous patent publication in that the anti-inflammatory agent content can be increased as detailed below. .

Examples of non-steroidal anti-inflammatory drugs used in the present invention include indomethacin, piroxicam, phenylbutacin, sulindac, ibuprofen, naproxen, diclofenac, acetylsalicylic acid, and the like.

Examples of natural albumin used in the present invention include:
Ovalbumin, serum albumin, plaque albumin,
Examples include α-lactalbumin, leu-cosine, phaselin, and levumelin, and ovalbumin is particularly preferred. Furthermore, in order to apply the composition obtained by the present invention to the field of pharmaceuticals where antigenicity is a problem, it is preferable to use human-derived albumin.

The anti-inflammatory agent comprising the non-steroidal anti-inflammatory agent-natural albumin composition of the present invention is prepared by first bringing natural albumin and the non-steroidal anti-inflammatory agent into contact with each other under high-speed stirring in the presence of an aqueous solvent, and then removing the aqueous solvent. or after dissolving the non-steroidal anti-inflammatory agent in fatty oil and/or fatty acid,
It can be easily produced by adding to an aqueous suspension of natural albumin, stirring at high speed, and then distilling off the aqueous solvent.

The concentration of the natural albumin suspension when producing this composition is not particularly limited, but it can be used at a concentration of at least 1% (W/V), preferably from 5 to 25% (W/V). The use of natural albumin relative to non-steroidal anti-inflammatory agents can also vary widely, but generally 5 to 100 parts of non-steroidal anti-inflammatory agent to 100 parts of natural albumin are used.
It is preferable to use a proportion of 1.0 parts.

Any aqueous solvent can be used as long as it dissolves natural albumin without denaturing it, but water is most preferred.

However, part of the water can also be replaced with a hydrophilic solvent such as methanol, ethanol, acetone, ethyl acetate, etc. Moreover, hydrophobic solvents such as chloroform, dichloroethane, benzene, etc. can also be used together with the above-mentioned water and hydrophilic solvents.

Although the reaction temperature and reaction time are not critical, it is generally advantageous to react both at a temperature at which natural albumin does not undergo thermal denaturation, preferably room temperature, for about 1 to 30 hours under high speed stirring, preferably at about 500 to 30 QQ Orpm. It is.

Furthermore, in a method in which the nonsteroidal anti-inflammatory agent is dissolved in fatty oil and/or fatty acid and then added to an aqueous suspension of natural albumin, the nonsteroidal anti-inflammatory agent is dissolved in fatty oil and/or fatty acid. It is preferable to use an organic solvent, and examples of the organic solvent that can be used include acetone, methanol, ethanol, chloroform, ethyl acetate, benzene, ether, dichloromethane, and THF.

In addition, in the production of the composition of the present invention, it is not necessary to use a solubilizing agent such as carboxymethylcellulose, gum arabic, dimethylformamide, dimethyl sulfoxide, etc., and a surfactant used in the production of albumin spherules is also required. Therefore, there is no fear of side effects caused by the inclusion of these solubilizers and surfactants in the non-steroidal anti-inflammatory drug-natural albumin composition. Fatty oils include olive oil, corn oil, coconut oil, soybean oil, sesame oil, etc., and fatty acids include C9 to C3.
゜ straight chain fatty acids can be mentioned.

The nonsteroidal anti-inflammatory drug and fatty oil and/or fatty acid are usually stirred at 15 to 65°C for about 30 to 120 minutes, and the organic solvent is distilled off by a method such as nitrogen gas injection or reduced pressure. It's advantageous.

The concentration of the non-steroidal anti-inflammatory agent dissolved in the organic solvent is not particularly limited, but is at least 0.5% (W/V),
It can be used preferably at a concentration of 1 to 10% (W/V).

Furthermore, the ratio of addition of the non-steroidal anti-inflammatory drug solution to fatty oil and/or fatty acid is not particularly limited, but is at most 100% (V/V), preferably 1 to 50% (■/
V) can be used.

After mixing in the above method, the homogeneous suspension obtained by high-speed stirring is used to remove the solvent by air drying, vacuum drying, drum drying, spray drying, freeze drying, etc. to obtain the desired powder form. Non-steroidal anti-inflammatory agent-natural albumin compositions can be obtained. This non-steroidal anti-inflammatory agent-natural albumin composition is one in which the non-steroidal anti-inflammatory agent and natural albumin at least partially form a hydrophobic bond, and scanning electron micrographs show that
For example, a hydrophobic conjugate obtained by spray drying has a continuous donut-shaped three-dimensional structure with an average particle size of 5 to 10 μm, and a hydrophobic conjugate obtained by freeze-drying has a continuous donut-shaped three-dimensional structure. In this case, it has been confirmed that the crystal has a three-dimensional structure in which plate-like crystals with an average size of 5 to 10 μm are stacked.

The non-steroidal anti-inflammatory agent-natural albumin composition of the present invention thus obtained has excellent absorption into the body and long-lasting properties when administered orally.

The following animal experiments demonstrate that the non-steroidal anti-inflammatory agent-natural albumin composition of the present invention has excellent absorption properties, reduced side effects, and excellent anti-inflammatory effects.

(1) Test method for the inhibitory effect of indomethacin-ovalbumin composition on carrageenan paw edema in rats A Hiro glass container was filled with neutral water, placed on an electronic balance, and the right hind limb of the rat was immersed up to the hairline. The increased weight was measured and the volume was added to the leg.

Is the rat a Wistar weighing 150-180g? Wist
After fasting for about 18 hours using 3 groups of 6 animals in 1 group of ar) type salt,
The foot volume was measured by the above measurement method and used as the pre-administration value.

As a sample, the indomethacin-ovalbumin composition obtained in Example 2 below was used as indomethacin for about 5
mg/kg suspended in 1% carboxymethyl cellulose sodium aqueous solution (abbreviated as 1% CMC) and indomethacin bulk powder 1% so as to be 5 mg/kg.
Q was suspended in CMG and administered orally at a rate of 5 ml per 100 g of rats. 1% λ-carrageenin (carrageenin) 30 minutes after oral administration.
) was dissolved in physiological saline and 0.1 ml was subcutaneously administered to the rat's right hind leg, and immediately thereafter 5 ml of water was orally administered. 1% λ-carrageenan administration #&1.The heel volume at 3.5 hours was measured, and the swelling rate and group average swelling rate of each individual, and the inhibition rate based on them were calculated using the following formulas.

Ta.

As a control, 1% CMC was added at 0.0% per 100g of rat.
A group in which 5 ml of the drug was orally administered was set up and compared with the sample administration group.

Δ -D Suppression rate (%) - X100 A: Administration volume B: Foot volume after administration C: Control group average swelling rate D: Sample group average swelling rate The results are shown in Table 1 below.

As is clear from Table 1, the indomethacin-egg albumin composition of Example 2 already showed a higher inhibition rate than the indomethacin bulk powder 1 hour after administration, and a very high inhibition rate even 5 hours after administration. It shows.

(2) Test method for gastric ulcer forming effect of indomethacin-ovalbumin composition Method of Kaibe et al. [Japanese Journal of Pharmacology (Japanese Journal of Pharmacology)
Macol, Vol. 2.9, p. 670 (1979)]. That is, two groups of 8 Wjstar male rats weighing 180 to 200 g were fasted for about 18 hours, and each of the indomethacin-ovalbumin compositions obtained in Examples 1 and 2 was given as indomethacin at 20%. 1% to make mg/kg
Carboxymethyl cellulose sodium aqueous solution (1% C
(abbreviated as MC) per 100 g of rat,
It was administered orally at a rate of 5 ml. In addition, as a control, indomethacin bulk powder suspended in 1% CMC at 20 mg/kg was administered in the same manner.

Seven hours after administration, all rats were killed with ether, and 1%
After injecting 8 ml of buffered formalin aqueous solution into the stomach, it was removed and
Next, the stomach was immersed in a % buffered formalin aqueous solution for 15 minutes, and then the stomach was incised along the tenryu. Under a stereomicroscope, the long axis (mm) of the damaged area (ulcer) on the gastric mucosa was measured, and the total was calculated as the ulcer. It was taken as a coefficient.

Table 2 A feature of the composition of the present invention is that when administered to the digestive system, local irritation side effects in the digestive system are reduced. From Table 2, it can be seen that the incidence of ulcers in the gastric mucosa of the indomethacin-ovalbumin compositions of Examples 1 and 2 was clearly reduced compared to the indomethacin raw wood. Furthermore, no side effects of these indomethacin-ovalbumin compositions were observed in other digestive organs.

Thus, the composition of the present invention can be orally administered as a drug having anti-inflammatory effects for the treatment and treatment of humans and other animals with bleeding.

When used as a drug, the composition of the present invention can be formulated into various forms suitable for oral or parenteral administration.
For example, the compositions of the present invention can be formulated as a medicament containing together with non-toxic pharmaceutically acceptable carrier materials commonly used for such drugs. , such drugs may be in solid form (e.g. tablets, capsules,
granules, powders, fine granules, dragees, lozenges, etc.), semi-solid forms (e.g. ointments, puffs, creams, suppositories, etc.)
and liquid forms (emulsions, suspensions, lowsilons, tinctures,
11 for any formulation form (spray, syrup, etc.)
It is possible to do 4M. Thus, non-toxic pharmaceutically acceptable carrier materials that can be used include, for example, starch,
Gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyalkylene glycol, p-hydroxybenzoic acid alkyl ester, simple syrup, ethanol, propylene Examples include glycol, glycerin, petrolatum, carbowax, and the like.

The agent may also contain other therapeutically useful agents, dispersants, antioxidants, preservatives, stabilizers, flavoring agents, binders, lubricants,
Salts, buffers, etc. can be included to alter the osmotic pressure.

The content of the composition of the invention in the medicament varies depending on its dosage form, but generally at a concentration of 5 to 100% by weight for solid and semi-solid forms, and 0.5% for liquid forms. It is desirable to contain the active compound in a concentration of 1 to 10% by weight.

The dosage of the composition of the present invention can be varied widely depending on the type of target bleeding animal including humans, the severity of the symptoms, the doctor's diagnosis, etc., but in general, the dosage is 1 to 10% per day.
1000mg/kg1 preferably 10-500mg/kg
It can be done. However, as mentioned above, depending on the severity of the patient's symptoms and the doctor's diagnosis, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range.

The above dosage can be administered once a day or in divided doses.

〔Example〕

Next, the present invention will be further explained by examples.

Example 1 After dissolving 3 g of indomethacin in 30 ml of ethanol, 600 ml of a 5 (W/V)% ovalbumin aqueous solution was added.
In addition to 1, the mixture was stirred at high speed at room temperature at about 2000 rpm for 30 minutes using a biomixer (model BM-4, newly manufactured by Nippon Seiki Seisakusho) to obtain a homogeneous phase.

After evaporating the ethanol in an evaporator while heating to 50-60°C, freeze-drying and indomethacin-
28.7 g of egg white and lupumin composition were obtained. The obtained indomethacin-ovalbumin composition had a plate-like three-dimensional structure with a longest particle length of about 10 μm, as shown in the scanning micrograph of FIG. 1.

Example 2 3 g of indomethacin was dissolved in about 60 ml of acetone, 100 ml of olive oil was added thereto, and the mixture was stirred at high speed for about 30 minutes at about 11,000 Orp. Then, zeolite was added and the mixture was heated to about 70 to 80°C.
The acetone was evaporated under nitrogen gas injection while heating to . On the other hand, 30g of ovalbumin was redistilled for 900m.
In addition to step 1, the mixture was stirred at high speed with a biomixer (Model BM-4, manufactured by Nippon Seiki Seisakusho) for about 30 minutes at about 11,000 Orp under water cooling to obtain a homogeneous phase. The ovalbumin double-distilled water suspension and the indomethacin-olive oil mixture were mixed by shaking using an eggplant-shaped flask, then stirred at high speed for about 2 hours at about 10,000 rpm in a biomixer under water cooling, and then mixed with a spray dryer (inlet temperature : Approximately 130 to 140℃, outlet temperature: approximately 70 to 80℃) to instantly dry indomethacin.
26.5 g of an egg albumin composition was obtained. The obtained indomethacin-ovalbumin composition had a continuous donut-shaped three-dimensional structure with an average size of 5 to 10 μm, as shown in a scanning electron micrograph of FIG. 2.

Example 3 18 g of ovalbumin was added to 400 ml of distilled water, and a homogeneous phase was obtained by stirring at high speed with a biomixer (Nippon Seiki Seisakusho, Model IBM-4) at about 11,000 Orp for about 30 minutes while cooling.

2 g of aspirin was dissolved in 20 ml of ethanol and added to the homogeneous phase. Approximately 1 at about 1100QQrp while further cooling
High-speed stirring was continued using a biomixer for hours, 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 18 g of an aspirin-ovalbumin composition having a uniform particle size.

Example 4 After dissolving phenylbutacin Ig in 3 ml of acetone, 200 ml of 5% (W/V) ovalbumin aqueous solution was added.
l and biomixer (Nippon Seiki Seisakusho! IBM-4 model) for about 30 minutes at about 1000 orpm near room temperature.
A homogeneous phase was obtained by stirring at high speed.

After evaporating the ethanol with an evaporator while heating it to 50-60°C, it was instantly dried with a spray dryer (inlet temperature: about 130-140°C, outlet temperature: about 70-80°C) to form phenylbutacin-egg white. 9.2 g of albumin composition was obtained.

Example 5 18 g of ovalbumin was added to 400 ml of distilled water, cooled, and stirred at high speed for about 30 minutes at about 1000 rpm and Qrpm using a biomixer (Model BM-4 manufactured by Nippon Seiki Seisakusho) to obtain a homogeneous phase.

2 g of piroxicam was dissolved in 100 ml of methanol and added to the homogeneous phase. While further cooling, high-speed stirring was continued using a biomixer at about 11,000 Orp for about 1 hour, 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 18 g of a piroxicam-ovalbumin composition having a uniform particle size.

Example 6 Add 18 g of egg white albumin to 400 ml of distilled water, and mix in Biomixer C at about 11,000 Orp for about 1 hour while cooling.
A homogeneous phase was obtained by high-speed stirring using a model E (Model BM-4 manufactured by Honseiki Seisakusho).

2 g of sulindac was dissolved in 100 ml of methanol and added to the homogeneous phase. The mixture was further cooled and stirred at high speed in a biomixer at approximately 11,000 rpm for approximately 1 hour, 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 about 18 g of a sulindaku egg albumin composition with a uniform particle size.

Example 7 Composition of Example 1 50g lactose
20g corn starch 20g crystalline cellulose
7g hydroxypropyl cellulose
1g Magnesium stearate 1.5g
Talc 0.500g [Operation] The composition of Example 1, lactose, corn starch and crystalline cellulose were mixed, and hydroxypropylcellulose dissolved in 3Qml of water was added thereto and thoroughly kneaded. This kneaded product was granulated and dried. Mix magnesium stearate and talc with the obtained granules and make one tablet 200m
It was compressed into tablets.

Example 8 Composition of Example 2 400g milk 12
300 g potato starch 270 g hydroxypropyl cellulose 3000 g [Procedure] Mix the composition of Example 2, lactose and potato starch, add hydroxypropyl cellulose to this and add 400 m of water.
1 g was dissolved and added, and thoroughly kneaded. This kneaded product was granulated and dried. It was then refined into granules and made into granules.

Example 9 Composition of Example 3 2500g lactose
400g hydroxypropylcellulose 0000g [Operation] The composition of Example 3 and lactose were mixed, and hydroxypropylcellulose dissolved in 10100O water was added and thoroughly kneaded. This kneaded product was granulated and dried. Thereafter, granulation was performed to obtain granules.

Example 10 Composition of Run N5 100g Milk 11
200g Balayea starch 50g crystalline cellulose
46g stearin magnesium
400g [Operation] The above ingredients were thoroughly mixed and 400mg each was filled into No. 0 capsules to prepare capsules.

〔Effect of the invention〕

As detailed above, the non-steroidal anti-inflammatory agent of the present invention -
An anti-inflammatory agent made of a natural albumin composition is obtained by stirring a non-steroidal anti-inflammatory agent and natural albumin in a predetermined medium at high speed, and has the industrial advantage of being easy to manufacture. It also has the advantage that when administered, it is easily absorbed and the gastrointestinal disturbances inherent to this type of anti-inflammatory agent are reduced.

[Brief explanation of the drawing]

1 and 2 are scanning electron micrographs of indomethacin-ovalbumin compositions obtained in Examples 1 and 2, respectively. Procedural amendment (method) June 23, 1985 1 Temple 3 no. Director 'α 2, Name of invention Relationship to the case Patent applicant name Nippon Highbox Co., Ltd. 4, agent address 104 Tokyo Kayanuma Building 802, 2-10-6 Shinkawa, Chuo-ku

Claims (1)

[Scope of Claims] 1. An easily absorbable anti-inflammatory agent with reduced gastrointestinal disorders, which is composed of a non-steroidal anti-inflammatory agent and natural albumin. 2. A nonsteroidal anti-inflammatory agent and natural albumin are stirred at high speed in the presence of an aqueous solvent, and then the aqueous solvent is distilled off to produce an easily absorbable anti-inflammatory agent consisting of a composition of a nonsteroidal anti-inflammatory agent and natural albumin. A method for producing an easily absorbable anti-inflammatory agent, characterized in that it obtains the following: 3. After dissolving the nonsteroidal anti-inflammatory agent in fatty oil and/or fatty acid, it is added to an aqueous suspension of natural albumin, stirred at high speed, and the aqueous solvent is distilled off to obtain a composition of the nonsteroidal anti-inflammatory agent and natural albumin. An easily absorbable anti-inflammatory agent and a method for producing the same, characterized in that an easily absorbable anti-inflammatory agent is obtained.