JPH0377822A - Liposome preparation - Google Patents

Abstract

PURPOSE:To increase the variety of drugs suitable for liposome preparation and to obtain a liposome preparation exhibiting therapeutic effect having high safety, stability and pharmaeodynamic action by dissolving a drug in crotamiton and converting the solution into liposome. CONSTITUTION:The objective liposome preparation contains (A) a drug soluble in crotamiton (crotonyl-N-ethyl-o-toluidine). e.g. an antimycotic agent such as clotrimazole, a non-steroidal agent such as indomethacin or a carcinostatic agent such as 5-fluorouracil and (B) 0.1-5wt.% (preferably 0.5-3wt.%) of crotamiton. The amount of the drug is determined according to the solubility of the drug in crotamiton.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel liposome formulation. For more information,
By dissolving drugs in crotamiton and making them into liposomes, we can expand the range of drugs that can be made into liposomes and improve their safety.
Stability: It has excellent medicinal efficacy. [Prior technology] Liposomes have a bilayer membrane made of lipids and closed vesicles with an aqueous phase inside, and have been widely used as a biological membrane model. In order to efficiently deliver drugs to the target site, drug delivery systems (D
Efforts are being focused on the development of DS. Liposomes are capable of retaining various drugs in their internal aqueous phase or membrane, so much research has been done on their use as drug carriers. However, conventional liposomes are limited to drugs that have a high affinity with lipids, which limits the drugs that can be used.

[Means for solving problems]

In view of these circumstances, the inventors of the present invention have made a conclusion after extensive research. By dissolving drugs in crotamiton and making them into liposomes, the range of drugs that can be made into liposomes can be expanded, and the safety, stability, and efficacy of the drugs can be improved. The present invention was completed after recognizing that it exhibits excellent therapeutic effects.That is, the present invention relates to a drug soluble in crotamiton and a liposome preparation containing crotamiton.The crotamiton used in the present invention has a chemical name of Crotonyl-
It is a common name for ethyl-o-toluidine, and is a hypoallergenic colorless to pale yellow oily liquid.

Widely used as an anti-pruritic agent. In addition, crotamiton has a high dissolving power for many drugs and has a high affinity for phospholipids. In the present invention, the amount of crotamiton used is 0.01-1011% by weight. Preferably 0.1 to 51i% by weight, most preferably
0.5~3! The concentration of crotamiton in L amount % is 0.
If it is less than 0.01% by weight, it is not possible to dissolve much of the drug;
If the amount of 101i is more than 101i, it is difficult to form liposomes.

The acute toxicity LD of crotamiton is 1600 in mice.
mg/kg, 1500 mg/k in rats
g, and is safe with low toxicity.

As the drug used in the present invention, any A/ drug can be used as long as it dissolves in crotamiton. Therefore, it is possible to encapsulate many drugs in addition to those that can be encapsulated in conventional liposomes. Examples of these drugs include, but are not limited to: antifungal agents (e.g., clotrimazole, miconazole, siccanin, virolnidoline, tolnaftate, etc.), nonsteroidal agents (e.g., ibuprofen, ketoprofen, indomethacin, bufexamac and their derivatives, etc.),
Steroids (e.g. dexamethasone, hydrocortisone, betamethacin, fluocinolone and their derivatives, etc.), anticancer drugs (e.g. 5-fluorouracil, mitomycin C, daunomycin, methotrexate, etc.), antibiotics (e.g. tetracycline, erythromycin, etc.), liver damage improvement agents (for example, glycyrrhizic acid, glycyrrhetinic acid and their derivatives), etc.

In the present invention, the amount of these drugs used is determined by the solubility of each drug in crotamiton.

For example, the solubility of clotrimazole in crotamiton at 25° C. is 5 g, and similarly the solubility of indomethacin is 7 g.

The liposome of the present invention is composed of crotamiton and a drug dissolved in crotamiton, as well as phospholipids and water.Surfactants and the like may also be used.

Examples of the phospholipids used in the present invention include soybean phospholipids, egg yolk phospholipids, hydrogenated soybean phospholipids, hydrogenated egg yolk phospholipids, synthetic phospholipids, etc., and they may be used alone or in combination of two or more. I can do it. The amount used is O61-10 for the mixture of crotamiton and drug.
It is added to double the concentration.

Examples of the stabilizer include cholesterol, glucose, amino acids, higher alcohols, and polyhydric alcohols. As a surfactant, for example, a nonionic surfactant or an ionic surfactant can be optionally added.

The liposomes of the present invention are manufactured according to conventional liposome manufacturing methods. For example, the target product is obtained by irradiating M-sonic waves to three components: a drug dissolved in crotamiton, phospholipid, and water. The obtained liposome is a spherical endoplasmic reticulum consisting of a single or multilayered bilayer membrane of phospholipid, and the drug and crotamiton are incorporated into the phospholipid membrane or the endoplasmic reticulum. In addition, for liposome formation, in addition to the ultrasonic method, methods such as VORT, EX mixer, surfactant removal and injection flow, French press, reverse phase evaporation, etc. may be selected as appropriate.
Depending on the manufacturing conditions, liposomes with a diameter of 20 nm = several μm can be obtained.

The liposomes of the present invention may be used for either oral or parenteral administration, and the dosage will be based on the dosage of the drug encapsulated in the liposomes.

〔Example〕

Next, the present invention will be further explained with reference to Examples, but the present invention is not limited thereto. The numbers in the formulations indicate weight %.

Example-1 Antifungal agent Crotamiton 1° 0 ■ Clotrimazole 1.00 Hydrogenated soybean phospholipid 4° 0 ■ Polyoxyethylene (40
) Hydrogenated castor oil 1゜0 3 0 Total 100.0 Ingredient ■ Chloro] Rimazole was added to component ■, heated and dissolved at 70°C, then added ingredient ■■■, heated to 70°C and treated with ultrasonic irradiation. Lubricate the liposomes.

Example-2 Antifungal agent Crotamiton 5.0 ■ Tolnaftate 2° 5 ■ Hydrogenated egg yolk phospholipid 5.00 Glycerin
10・ 07 5 Total 100.0 Liposomes were prepared in the same manner as in Example-1.9 Example-3 Antifungal agent ■ Crotamiton 0° 1 ■ Pyrrolnidoline 0.01 ■ Hydrogenated soybean phospholipid 2° 0 ■ 1゜ 3 Butylene glycol 3. 0489 Total ioo, 0 Liposomes were prepared in the same manner as in Example-1.L Example-4 Non-steroidal agent ■ Crotamiton 2° 0 ■ Indomethacin 1,0 ■ Hydrogenated soybean phospholipid 2.00 Cholesterol
0.1419 Total 100゜0 Ingredient ■Indomethacin is added to component ■ and heated to 80°C. Ingredient ■■■ is added, heated to 70°C, and liposomes are prepared by ultrasonic irradiation.

Example-5 Non-steroidal agent Crotamiton 0゜ 5 ■ Ibuprofen 0.1 ■ Hydrogenated egg yolk phospholipid 3.0 ■ Polyoxyethylene (40) Hydrogenated castor oil 0.361 Total 100゜0 Same as Example-4 Preparation of liposomes Example 6 Steroid ■ Crotamiton 0.5 ■ Prednisolone acetate 0.2 ■ Hydrogenated egg yolk phospholipid @ 1゜0 ■ Cholesterol
0.05825 Total 100.0 Dissolve component (■) in 30rnl of chloroform and place in an eggplant-shaped flask. Chloroform is distilled off using an evaporator. After drying this in a desiccator for 2 days, heat it to 70℃ and add the ingredients.
Liposomes are made into tmm by shaking on a Vortex mixer and peeling off the thin film.

Example-7 Anticancer agent ■ α Tamiton 0° 5 ■ Mitomycin C001 ■ Hydrogenated soybean phospholipid 1. O ■ Propi 1
/ N Glycol 5.034 Total 100.0 Add ■ to component ■, dissolve at 40°C, add to component ■■■, and prepare liposomes by ultrasonic irradiation.

〔Effect of the invention〕

The effects of the present invention are that by dissolving drugs in crotamiton and forming them into liposomes, the range of drugs that can be encapsulated in liposomes can be expanded, and the drug can be used by either oral or parenteral routes of administration. .

Next, the effects of the present invention will be described below.

Experimental Example-1 For the liposome of Example-1 and Comparative Example-1 below, 10 Wistar rats (body I1
After 1150 g m) back 5X10 crrf! Tri
chophyton mcntaHrophytes
Apply 0.3 ml of this suspension and infect the patient.24 hours before infection, the absorbance is 0. Fungal suspension showing 4 and Nervina nutrient brot
The mixture was prepared by mixing h with a ratio of 2:1 and incubated at 25°C. Treatment starts from the 3rd day after infection.
02 times for 7 days, Oo 5g of Example-1 and Comparative Example-1
Rub it on the infected area and visually observe changes in the condition of the infected area.The results are shown in Table 1.

Comparative Example 1 A sample was prepared by blending as it was without ultrasonic irradiation according to Example 1. When used, the precipitate was thoroughly stirred and dispersed.

From the results in Table 1, it was found that by dissolving the antifungal agent clotrimazole in crotamiton and forming it into liposomes, the dermatophyte Triehophyton 5.
It can be seen that it is effective, showing good therapeutic effects against A. rophytes. In addition, similar good results were obtained in Examples 2 and 3. 1 Animal Experiment Results Experimental Example-2 A carrageenan paw edema suppression test was conducted on Example-4 and Comparative Example-2 below.
0.05 ml of 1% carrageenan as an inflammatory agent was subcutaneously injected into the hind paws of the rats (before and after), and 250 mg/kg of each rat was administered 2 hours after carrageenan administration.
Administered intravenously. Edema volume was measured 4 hours after carrageenan administration. The results are shown in Table 2.

Comparative Example-2 From Example-4, indomethacin prepared by blending as is without ultrasonic irradiation, and from the results shown in Table 2, liposomal indomethacin showed a significant inhibitory effect compared to untreated foot ulcers. , it can be seen that a strong suppressing effect was obtained even for the comparative example, indicating that it is effective. Similarly, good results were obtained in Example-5.

Table 2: Effect of carrageenan on suppressing paw edema.Itching sensation was described. Table 3 shows the results.
Shown below.

Comparative Example-3 From Example-6, ingredients ■■ and ingredients ■■■ were prepared by mixing them at 80°C. According to the results in Tables 3 and 4, prednisolone acetate was made into liposomes and blended to treat dermatitis. It can be seen that the drug shows excellent efficacy against cancer and has few side effects.

Table 3 Experimental Example for Efficacy Determination-3 For a clinical trial, volunteers were recruited, and among them, 30 people who appeared to be suffering from eczema or dermatitis were tested for Example-6 and Comparative Example-3 below. Apply an appropriate amount to the infected area once a day and observe the results for one week.
Shown in 2.

Regarding side effects, the skin corners (L, margin table below irritation during application, 4 side effects) were prepared.

From the results in Table 5, it can be seen that liposomal mitomycin C has a significant life-prolonging effect even on the untreated comparative example and is effective.

Table 5 Experimental Example 4 for Life Extension Effect Regarding Example 7 and Comparative Example 4 below, 30 SD rats, 9 weeks old, were subcutaneously implanted with rat liver cancer-like AH-66 to form tumors.6 Liver cancer-like rats After subcutaneously implanting Example 7 and Comparative Example 4 below, 100
Mg/kg was administered subcutaneously around the tumor twice a week.An untreated rat group was also set up as a control.
The survival effect on the animals was measured and the results are shown in Table 5.

Comparative example-4

Claims (3)

[Claims] (1) A liposome preparation characterized by containing a drug soluble in crotamiton and crotamiton. (2) The liposome preparation according to claim (1), characterized in that it contains 0.1 to 5% by weight of crotamiton. (3) The liposome preparation according to claim (1), wherein the drug is an antifungal agent or a non-steroidal agent.