JPS5859912A - Fat emulsion of analgesic and antiphlogistic substance - Google Patents

Abstract

PURPOSE:To obtain an O/W type fat emulsion administrable by intravenous injection, free of side effects, and useful as the titled drug, by emulsifying an analgesic and autiphlogistic substance selected from ibprofen, flufenamic acid and ketoprofen. CONSTITUTION:An extremely stable O/W type fat emulsion administrable by intravenous injection and accordingly, free from side effects, such as gastroenteric disorder, and containing a nonsteroid analgesic and antiphlogistic substance selected from ibuprofen, flufenamic acid and ketoprofen of foumulaI-formula III, is prepared by emulsifying an active amount of the drug component toghther with preferably 5-50 W/V% soybean oil and 1-50pts.wt., based on 100pts.wt. of the soybean oil, of a phospholipid in a proper amount of water. If necessary, the emulsion is added with <=0.3 W/V% 6-22C fatty acid or its physiologically acceptable salt as an isotonic agent, emulsion assistant or emulsion stabilizer, and/or <= 0.5 W/V% cholesterol or <=5 W/V% phosphazinic acid as a stabilizer.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a fat emulsion containing a nonsteroidal analgesic and antiinflammatory substance.

More specifically, the present invention relates to a fat emulsion containing in fat particles at least one pain-relieving and anti-inflammatory substance selected from the group consisting of the following formula σD1 ketopro7ene (III).

Many of the non-steroidal analgesic and anti-inflammatory substances that have been developed so far have been formulated as oral preparations due to their physicochemical properties, and only a few examples exist in the form of suppositories.

However, these anti-inflammation products JX contain N for each yuzu organ.
Causes effects, especially gastrointestinal disorders. This gastrointestinal disorder is often caused by the direct action of pheromones on the walls of the gastrointestinal tract, and a preparation that can avoid these problems is awaited.

From this point of view, the present inventors have developed Saba 1F4 that is not for production.
As a result of extensive research in order to obtain an anti-inflammatory drug, I was determined to create a silent *r emulsion containing the above-mentioned satisfactory non-steroidal anti-inflammatory agent - IjL. Furthermore, the present inventors+i differ from conventional sheathing agents in that the fat emulsion has the ability to cause phagocytosis of macrophages, lymphocytes, etc. that gather at the site of inflammation, specifically induce drug wrinkles at the site of inflammation, and It was found that it was possible to maintain the sustainability of the drug by administering it in the same manner as @ ridge, and also found that such a fat emulsion does not cause the N effect that conventional copper has.

The present invention was developed based on the above-mentioned initial research, and its purpose is to suppress non-steroidal threads. 8 flame 1JkL
An object of the present invention is to provide an oil-in-water fat emulsion obtained by t-emulsification.

Another object of the present invention is to provide an intravenously injectable non-steroidal anti-inflammatory agent without side effects.

Still another object of the present invention #i A non-steroidal drug that maintains viscosity at the inflamed area for a longer period of time than the conventional formulation and is capable of focusing differently on the moxibustion area. The object of the present invention is to provide a novel formulation with anti-inflammatory properties.

Other objects and aspects of the present invention will become apparent from the following description.

According to the invention, at least m-
Results: An oil-in-water fat emulsion made by emulsifying inflammation-active substances, especially an effective amount of soybean oil, soybean oil, 5 to 50%
% (V/V), good'lL<iJl~30% (W/V
), soybean oil used in the fat emulsion of the present invention, which provides a fat emulsion obtained by emulsifying violet phospholipids with a weight ratio of 1 to 50, preferably Fi, 5 to 30, in pure water. is 1. ! ! , the purity of Japanese soybean oil is preferable, for example, it is t11'11ml1 soybean mt water A'l
lkmffi (H, J, Li:p8fJ, MUML
otx Ch@m1st, BOC-, 27, 422-4
23 (1950)), etc., and high purity f# soybean fm obtained by further InI production (99.9% as purity nitriglyceride, diglyceride and monoglyceride).
9% or more).

Examples of the phospholipids used in the present invention include phos-7-acylcholine-1-phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, sphingomyelin fx, tocahn, and tL, particularly preferably phosphatidylcholine. Of course, a mixture of these may be used. It is preferable that such phospholipids are also purified, and the purification method includes, for example, a fractionation method using an organic solvent. When using egg yolk phospholipid jiL as a phospholipid, the glaze #! The situation is as follows.

Egg yolk phospholipid 13011 cold n-hexane 200- and cold acene) 100 After dissolving al#ζ, stir) Gradually add 1170 ml of cold acene) and filter off the insoluble eyelids (2
) and again dissolve in cold n-hex/260- and cold ascent x3omac. Under stirring, believe again) 1
170 Recommended jk was added, the non-#- was collected by filtration, the solvent was distilled off, and the mixture was dried! & Satoshi 6011.

Contains 70 to 8 degrees of phosphatidyl coria, 12 to 25 degrees of phosphatidylethanolamine,
Other phospholipids include phos-7 atidylinositol, phosphatidylcorian, and sphingomyelin. (D, J-Hanah-an et al.
J, Biol, Ch@mp 192.
62.3-62g (1951)).

The fat emulsion of the present invention has a history of Ll, 3*(W/V)
It may contain as an emulsifying agent a fat having 6 to 22 carbon atoms, preferably 12 to 2 carbon atoms, or a physiologically acceptable salt thereof. M), preferably 0.1 C (W/V) or less of violet cholesterol or 5 ''('/'), preferably 1 C (W/V)
//V) The following phosphatidic acids may be enriched as stabilizers.

The stabilizer is used to prevent fat particles from bonding together and increasing their particle size.Fatty acids with 6 to 22 carbon atoms as emulsification aids can be used if they can be added to pharmaceuticals. The fatty acid may be either straight chain or branched, but straight chain fatty acids are preferably used. In addition, natural fatty acids are conveniently used.Specific examples of preferred fatty acids include stearic acid, oleic acid, linoleic acid, valmitic acid, lylunic acid, myristic acid, etc.Salts of the above-mentioned fatty acids include physiological Acceptable salts include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), etc.0 Cholesterol and phosphatidic acid can be used for medicinal purposes only. Can be used.

In order to make the emulsion isotonic, a commonly used isotonic agent such as glycerin, glucose, norbitol can be added. tlI:
Non-steroidal thread jJK4 mountain to shoulder? A-flame 9 Mushin's shoulder young police are different depending on the form and purpose of the emulsion.
01~1 (1(W/V),'lfl L < rr
0.1~. 5 h (W/V).

The averageness of the moxibustion moxibustion proboscis macular rib emulsion according to the present invention is 1
．． It is preferable that it is 0μ or less.

A fat emulsion of such a particle size is passed through a conventional homogenizer, such as a pressure jet homogenizer or an ultrasonic homogenizer. First, a certain amount of soybean gamma, phospholipids, a non-steroidal anti-inflammatory agent with analgesic and anti-inflammatory properties, and diluent additives such as cholesterol or phosphatidine M as a stabilizing agent are required. A water-in-oil dispersion is prepared by mixing and heating the mixture and homogenizing it with the above-mentioned homogenizer, and then adding the required amount of water and homogenizing it with the above-mentioned homogenizer. It is easily produced by converting it into an oil-in-water emulsion. (reference:
R.P., Gayer et al., J.Am.
Ollchew, 5ac-p 32. 3 6
5-37 (L, (1950)).

Stabilizers and tonicity agents may be added to the resulting emulsion to ensure that the fat emulsion of the present invention is extremely stable, for example - rheumatoid arthritis,
- It is useful for treating joint pain, arthritis, trauma, and unresolved chain removal after surgery.It is preferably administered non-daily, especially intravenously. The dosage for adults is generally 0.1 to 1000-7 times as an emulsion, although it varies depending on the administration trz, dosage form of administration Ik4ki111, symptoms, etc.

The present invention will be explained in detail with reference to experimental examples and examples, but the present invention is not limited thereto.

Experimental example 1 4#! The LD and θ values of the formulation of the present invention obtained in Formulation Example 1 when administered intravenously to rats are 200 swj/kg body weight or more as a 10-fat emulsion, and 150 swj/# body weight or more as a 205 kI fat emulsion, If you use regular rapid injections, hemolysis and urination will be completely unbearable.

Experimental Example 2 A dIi strain (Q: zo-2aI) was used as an animal, and a formulation according to the method described below was intravenously administered.As a result, LDsolB by intravenous injection was 195 ml/#.

Experimental Example 3 A procedure similar to that of Experimental Example 1 and 1ρj was performed except that the formulation of Example 4 was used instead of the formulation of Example 1. As a result, the LD&@ value after intravenous injection was 15 B - rl/ I went on a ride.

Experimental Example 4 All operations were carried out in the same manner as in Experiment f1, except that the formulation of Example 7 was used in place of the formulation of Example 1. As a result, the LD and o value after intravenous injection was 130 wn/double.

Experimental example 5 Main issue #! A comparative experiment was conducted regarding the in vivo activity of Preparation A. The drugs to be administered were an emulsified ibuprofen preparation and buried saline prepared according to Example 1 below.The U animals were Wistar Keto (male: 5 per house, body weight 1801). Method: The drug was administered intravenously. In the experiment, rats were made to develop carrageenan floaters, and young mulberry fruits given to them were compared. Force 2 Genin Floating is 0.0% of carrageen dissolved in physiological saline. The onset of the disease was induced by administering IJlj to the sublimb of the limb. ◎30 minutes after administration of the drug μ carrageenan, 1 #/ml or 10 rl/h of the drug was administered to the tail vein, and the effect was measured by measuring the volume of the hind limb over time. I did it.

The results are as shown in Figure 1, where M2rL is the ibuprofen 10 wag/muV administration group, Ml is the same drug 1 mV# administration group, and B is the physiological saline 0.
This is a 14-dose solution.

As is clear from Figure 1, the ibuprofen-containing 1L preparation had a tC of 1 ml/compared to the control saline solution.
#Clear suppression of carrageenan edema was observed in La Yo Pak.

Experiment f116 A comparative experiment was conducted regarding the sustainability of the can body FF3 activity of the present kJi4 preparation. The flufenamic acid emulsion prepared in Example 4 of & and physiological saline were used as the drugs to be administered. The animals used were Wistar rats (5 rats, 1N, 180R), and the drug was administered intravenously. In the experiment, rats were made to develop carrageenan floaters and the effects of the test drugs were compared. Carrageenin edema was induced by administering 0.111 rlf of 1% carrageenan in physiological saline to hind leg paw-1. The drug was administered to the wing vein 30 minutes after carrageenan administration.
swf/# was administered, and its effects were measured over time by measuring hindlimb volume.

As a result, the structure shown in Fig. 2, A
2Fi flufenam@10sf/# administration group, M1 is the same agent 1 my/# administration group, and B is the physiological saline 0.1 ml administration group.

As is clear from FIG. 2, the flufenamic acid-containing emulsified preparation is different from the control physiological jI! :1 ml compared to salt water
The carrageenan edema was clearly suppressed in the /41 administration group.

Experimental Example 7 A comparative experiment was conducted regarding the sustainability of the in vivo activity of the formulation of the present invention. The administered drug is the fruit Th? An emulsified ketoprofen preparation prepared in II7 and physiological saline were used. The wJ items were Wistar rats (pheasant: 1l-5 animals,
Approximately 18(1) iris was used, and the administration method was intravenous administration of the drug. In the experiment, carrageenia edema was caused in rats, and the efficacy of the test drug was compared to 7. Carrageenia edema is 0.1114 of 1% strength 2 genin dissolved in physiological saline? : Caused by administration under the hind limbs. 30 minutes after administration of carrageenan, the drug should be administered to the ground at 1 me/kll or 1
0 Mf/I was administered, and its effects were measured over time by measuring hindlimb volume.

The results are shown in Figure 3. In Figure 3, the liver is treated with Mutti Ketoglo 7g 10IwI/#, ml is the same drug Lawn/At administration group, and B is the physiological saline 0.1- This is the administration group.

As is clear from FIG. 3, the ketoprofen Genin emulsion formulation significantly suppressed the force 2 genin float Ii1 in the lIwI/# administration group compared to the control physiological saline.

Example 1 Refined soybean oil 100. Ojl*i egg yolk phospholipid 12oI
I, Ibuprofen 1. O1t: Dissolve by heating at 50-80°C. Furthermore, the purified egg yolk fat is uniformly dispersed in a homogenizer. Next is distilled fishing 700
di and 9, and glycerin 25IIi are added thereto, and heated Gs to make a homogeneous solution. The ibuprofen and purified egg yolk phospholipid-containing v# soybean oil is placed in an aqueous glycerin solution, and the metal cap is made up to 1 ton with distilled water, followed by rough emulsification.

After rough emulsification, use a high-pressure injection emulsifier to create a W film pressure of 120 Ky.
The emulsification is carried out for about 1-1.5 hours under a total pressure of 560 Kfl/cd/cd s. Liquid temperature during emulsification: 65-75
Keep at ℃. This resulted in a fat emulsion containing ibuprofen. This emulsion was a confinement emulsion with an average grain size of 0.2 to 0.4 .mu. and contained no grains larger than 1 .mu..

Example 2 Oleic acid 0.5 Ii and phosphatidine #ko,s
yt%n! ! A fat emulsion containing ibuprofen having analgesic and anti-inflammatory activity was obtained by carrying out the same treatment as in Example 1 except that egg yolk lecithin and ibuprofen were added to purified soybean oil.

Example 3 Cholesterol 6,st* was added to the phosphatidic acid residue in Example 2 and treated in the same manner as in Example 2 to obtain a fat emulsion containing ibuprofen'ft having analgesic and anti-inflammatory activity.

Example 4 The same procedure as in Example 1 was carried out, except that flufenam was added instead of ibuprofen, and a fat emulsion containing flufenamic acid, which had a role in the moxibustion activity of Sabakiku, was added.

Example 5 The same procedure as in Example 2 was carried out except that flufenam mt-m was added instead of ibuprofen to obtain a flufenamic acid-containing fat emulsion having post-analgesic τ1 activity.

A fat emulsion containing flufenamic acid having analgesic and anti-inflammatory activity was obtained by carrying out the same operation as in Example 3, except that all of the flufenamic acid was added instead of ibuprofen.

Example 7 The same procedure as in Example 1 was carried out, except that ketoprofen was added instead of ibuprofen, to obtain a ketoprofen-containing fat emulsion exhibiting 5*rR flame activity.

Example 8 A fat emulsion containing ketoprofen having analgesic and anti-inflammatory activity was obtained by carrying out the same operations as in Example 2 and iiJ, except that ketoprofen was added to the ibuprofen substitute in Example 2.

Example 9 The same procedure as in Example 3 was carried out except that ketoprofen was added instead of ibuprofen in Example 9113, to obtain a ketoprofen-containing fat emulsion having analgesic and anti-inflammatory activity.

Example 10 Purified egg yolk phospholipid in Example 1 12. Purified egg yolk phospholipid 51i24. Except for adding Of.
implementation? Example 11 In which a fat emulsion with analgesic and anti-inflammatory activity was obtained by carrying out the same operation as in Example 111. Example 12 The same procedure as in Example 4 was carried out except that 24.01 t of purified egg yolk phospholipid was added instead of Of, and a fat emulsion containing flufenamic acid having analgesic and anti-inflammatory activity was prepared. Phospholipid 12.H-made egg yolk phospholipid 24. instead of 01. A ketoprofen-containing fat emulsion wlF8, which commands analgesic and extinguishing activity, was prepared by performing the same operation as in Example 7, except for adding Of.

[Brief explanation of drawings]

Figures 1, 2, and 3 are graphs showing the anti-inflammatory effects of ibuprofen, flufenam Wl, and chlorophyllofene-containing fat emulsions according to the present invention, respectively. Procedural amendment (spontaneous) Patent Application No. 159227 of 1988 Number of inventions increased by b11 due to amendment of 541 6h11 None 7 Camphor tree in “Detailed description of the invention” and “Brief description of drawings” in the specification subject to amendment - 8 Contents of the amendment (1) In the last line of page 5, line 1 of page 6, line 3 of page 6, and line 4 of page 6 of the specification, the word "Ascent" has been replaced with "acetone". 0(2) On page 8 of the circular, line 6 from the bottom, correct the phrase ``1 to heat it to form a solution,'' to ``heat it.'' (3) In the 5th line from the bottom of page 8 of the same document, "water-in-oil type" is corrected to "homogenization." (4) Delete "conversion" in the second line from Douyou No. 8 No. 0. (5) Add r 200dAff to the fourth line from the bottom of page 9 in the same No. 4.
Correct it to J and total r 100d/KfJ. (6) In the third line from the bottom of page 9 of the same leaf, it is corrected to ``r150m+φt'' to r80d/KPJ. (7th grade, page 14, line 4 of the same book says "rl, 0#J")
Corrected to 2.09 J. (81 In the first line of page 15 of the same book, the term ``lecithin'' is corrected to ``phospholipid.'' , Rat carrageenan edema suppression experiment 7
The result was shown as follows.

Claims (1)

[Scope of Claims] (1) At least one member of the group consisting of ibuprofen, flufenamic acid, and ketopro7ene
〇 (2) Effective amount O anti-inflammatory agent, soybean oil 5-50 t (Vv)
)S Claimed scope of the invention is made by emulsifying a phosphorus MiI member of 1 to 50 phosphorus in a weight ratio of 1 to 50 in soybean oil to 100 ml of soybean oil in violet water.
1) The fat emulsion described in item 0 (2) The fat emulsion containing the isotonizing agent in the range of bone rods and Q) lance distribution. (4) 0.3 meeting (W/V) t”toto carbon as ~2
2 (/, + Supplementary formula containing fatty acids or physiologically acceptable salts thereof as an emulsification aid or emulsion stabilizer)
Part A (2) Fat emulsion. (Excellent) The fat emulsion according to claim (2), wherein O cholesterol of 0.56 (II/V) or less or phosphatidic acid of 5% (w/v) or less is added as a stabilizer.