JPH0469331A - Sustained release type pharmaceutical emulsion - Google Patents

Abstract

PURPOSE:To provide the title pharmaceutical preparation consisting of an O/W pharmaceutical emulsion containing polylysine. CONSTITUTION:Medicinal substances to be provided as sustained release type are added to, mixed with, and dissolved in a mixture of a fatty oil, emulsifier, and, where needed, coemulsifier and/or stabilizer, and water is added to the resulting solution followed by homogenization into an O/W emulsion, which is, in turn, admixed with a phosphoric acid buffer solution of polylysine at a concentration of 1 X 10<-9> to 1 X 10<-5> (pref. 1 X 10<-8> to 1 X 10<-6>)mol/l at the weight ratio of 1 : 1, thus obtaining the objective pharmaceutical preparation. Said O/W emulsion is pref. prepared so as to come to <=20wt.% in the fatty oil content, using 2 - 20pts.wt., per 100pts.wt. of said fatty oil, of the emulsifier and an appropriate amount of water.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to sustained release agents and sustained release emulsion preparations. More specifically, the present invention relates to a sustained release emulsion formulation for an O/W emulsion formulation containing polylysine as an active ingredient and an O/W emulsion formulation containing polylysine.

[Conventional technology]

In recent years, with the development of pharmaceutical science and medical technology, the influence of drug administration on living bodies has attracted attention. Therefore, especially in the pharmaceutical field, DrugDelivery
System (hereinafter abbreviated as DDS), that is, the use of carriers to transport physiologically active substances, has led to active research into the development of new dosage forms for the purpose of sustained drug release and targeting to target sites. It is being done.

Emulsion CJ and Cl1n have already been used as DDS preparations.
, Pharm, I: 11 27 (1976)), molecular assemblies such as liposomes, microspheres, and microspheres have been prepared, and their cleavage characteristics have been reported.

Furthermore, the in vivo compatibility of DDS preparations has recently been studied, and the safety of emulsions based on fat emulsions, which are already in clinical use, has been established when administered in vivo [Japan Infusion Co., Ltd. academic journals,
Yu, 126-134 (1969)). Therefore, from this point of view as well, emulsion preparations are considered to be useful as carriers.

Many reports have been made regarding the drug release characteristics of such emulsion preparations.

For example, Cajkovac (Acta Pharm9
．． Tech,, 30. 248 252 (1
[984)] is an emulsion type in which the amount of drug released differs depending on the content of the emulsion oil layer, and as the content decreases, the release increases, and the phase change from the W10 type to the O/W type accelerates the release. The relationship between release rate and release rate is reported. In addition, Yamama et al. [Pharmacology, 48, 285
-290 (1988)] is a multiple emulsion (0/W10W/○/W) and a single emulsion (○
/W.

In vitro, the release amount of the Wlo and O/W10 types was suppressed to 1/2 compared to the 0/W and W10/W types, and the release characteristics were determined by the properties of the external phase. It was shown that in viv
It has also been reported that sustained release effects were observed for each emulsion type of o.

[Problem to be solved by the invention]

However, there are few reports investigating the influence of the physicochemical properties of the oil phase on drug release characteristics. In emulsion formulations, the properties of the oil phase and drug interaction are major factors that determine the release rate, so it is considered important to clarify this issue.

[Means for Solving the Problem] The present inventors prepared emulsions using various triglycerides consisting of a single fatty acid in the oil phase, and when examining the influence of the carbon number of the fatty acid on drug release, the basic αD-polylysine (hereinafter referred to as PL), which is a polymer of amino acids
By coating the surface of emulsion particles with polylysine (abbreviated as ys or polylysine), they discovered a sustained release effect on drug release from an emulsion, and completed the present invention.

That is, the present invention relates to a sustained release agent for O/W emulsion preparations containing polylysine as an active ingredient, and a sustained release emulsion preparation comprising O/W emuldigone preparations containing polylysine.

The sustained-release emulsion preparation of the present invention is a conventional O/W (oil-in-water) emulsion containing a drug to be sustained-released and polylysine. The O/·W emulsion is composed of fats and oils, emulsifiers (emulsifiers and stabilizers may be added as necessary), drugs, and water, and is sustained-released by adding polylysine to it.

Examples of fats and oils include natural oils such as soybean oil, sesame oil, corn oil, safflower oil, almond oil, olive oil, turmeric oil, coriander oil, and caustic oil, and synthetic oils such as medium-chain fatty acid triglyceride and triacetin. In addition, vitamin E, dibutylhydroquine toluene (BHT),
Antioxidants such as butylated hydroxyanisole (B) (A) may also be added.

Examples of emulsifiers include phospholipids and nonionic surfactants. Examples of phospholipids include lecithin (phosphatidylcholine), phospholecithin (lysophosphatidylcholine), phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingomyelin, phosphatidic acid, hydrogenated lecithin or mixtures thereof.

Examples of nonionic surfactants include polyoxyalkylene copolymers, polyalkylene glycols, hydrogenated castor oil polyoxyalkylene derivatives, castor oil polyoxyalkylene derivatives, and the like.

Examples of emulsifying aids include stearic acid, oleic acid,
Potassium salts or sodium salts of C10-24 fatty acids such as linoleic acid, palmitic acid, lylunic acid, and myristic acid are mentioned. Note that the amount of these used is desirably 0.3% or less of the entire emulsion.

Examples of stabilizers include cholesterol and phosphatidic acid, which are used in amounts up to 1% of the total emulsion.

Various drugs can be used as examples of sustained-release drugs. For example, anti-diabetic drugs such as glipitide, gliclatide, and ciglitazone, vitamins such as vitamin A, vitamin K, and vitamin D, anti-aggregating agents such as heparin, cabexatomesylate, suloctidil, nafazatrom,
Antithrombotic agents such as picotamide, heparin-oligosancalide, antithrombin■, lipid-lowering agents such as beclobrate, pezafiprate, etofibrate, fenofibrate, vasodilators such as molsodomine, hydralazine, dihydralazine, nicorandil, diltiazem, flunarizine , calcium channel blockers such as gallopamil, veravamil, nifedipine, nicardipine, nimodipine, nitrendipine, lidoflazine, nildipine,
Antihypertensive agents such as captopril, enalapril, minoxidil, dihydroergotoxine, dihydroergotoxin-mesylate, endralazine, triamterene,
Diuretics such as hydrochlorothiazide, furosemide, biretanide, metolazone, peripheral vasodilators such as puflomedil, minoxidil, cadralazine, probentphylline, β-medicines such as talinolol, propranolol, atenolol, metoprolol, nadolol, pintocol, oxprenolol, rapetalol -Frotzka-, testosterone, testosterone undecanoate, progesterone, pregnenolone, corticosterone, cortisol, cortiscin, prednisolone, methylprednisolone, steroid hormones such as dexamethasone, prostaglandin E1, alprostadil, carboprost, evoprostenol , prostaglandins such as sulprostone, cefamandole, cefmetuxime, cefoperazone, cephalexin, cephalexin, cephalothin, cefazetone, cefmetuxime, cephalexin, cefoxitin, cephalothin, fosmidomycin, fosmidomycin, tetracycline, chlortetracycline and macrolide antibiotics material,
Antibiotics such as amino sugar antibiotics, gross hormones,
7) 1-lopine, somatostatin, insulin, calcitonin, parathyroid hormone (PTH), calcitonin gene-related peptide (CORP), glucagon,
Secretin, polypeptide hormones such as ACTH-LH-RH, α-interferon, β-interferon,
Polypeptides such as T-interferon, TNF, IL, etc., Corynebacterium balm (Coynebak
erium Paruum), Hepatis B vaccine (Hepatis BVaccin), Lactobacillus vaccine (Lactobacillus Va
ccin), Pneumococcal vaccine (Pneum
vaccines such as ococcal vaccin), bioactive polypeptides or proteins such as urokinase, chlormethine, cyclophosphamide, melphalan, chlorambucil, busulfan, thioteha, methotrexate, 5-flururacil, cytarabine, 6-mercaptopurine 6-naoguanine, Vincristine, Vinplastin, Vindesine, Actinmycin D, Mitomycin C, Mitramycin, Doxorubicin,
Antitumor agents such as pleomycin, cisplatin, procarbazine, and nystrumstine, antirheumatic agents such as indomethacin, diclofenac, ibuprofen, ibuproxam, ketoprofen, vilprofen, and suprofen, ketotifen fumarate, procaterol,
Examples include antiallergic agents such as tiaramide and tranilast, sleep sedatives such as flurazeham and lorazeham, and psychoactive agents such as oxazepam, diazepam, and promazepam.

The sustained-release emulsion preparation of the present invention includes the above-mentioned oil and fat, an emulsifier, and an emulsification aid and a stabilizer as necessary.
It is prepared by adding the drug to be sustained-released, mixing and dissolving it, adding water and homogenizing it to form a 0/W emulsion, and adding a phosphate buffer solution of polylysine to this and stirring.

The 0/W emulsion can be prepared by a conventional method using the emulsifier and oil as materials. In detail, for example, prepare 100 parts of soybean oil or sesame oil as an oil and 5 to 20 parts of ready-made purified lecithin as an emulsifier, preferably 6 to 18 parts, optimally 12 parts, add the drug to this, All you have to do is dissolve it and add an appropriate amount of water to it so that the amount of fat and oil is 20% or less compared to the amount of water.
Preferably, the ratio of oil and water to 100 parts to 500 to 5000 parts may be used. Then, it is coarsely emulsified using a homomixer at about 80° C., and then finely emulsified using a homogenizer. As the homogenizer, a commonly used homogenizing device such as a pressurized injection homogenizer or an ultrasonic homogenizer may be used. If necessary, emulsifying aids such as stearic acid, oleic acid, linoleic acid, palmitic acid, lylunic acid, myristic acid, etc. having 10 to 2 carbon atoms are added.
4 fatty acid or its alkali metal salt such as sodium salt or potassium salt at 0.3% or less Stabilizers, such as cholesterol or phosphatidic acid at 1% or less, tonicity agent,
For example, glucose or glycerin may be added. A sustained release O/W emulsion preparation is prepared by mixing polylysine, for example, in a phosphate buffer solution, with the O/W emulsion thus prepared in a ratio of emulsion:polylysine of approximately 1:1. The concentration of the polylysine solution added is 1 x 10-5 to 1 x 10-5 in sustained release emulsion formulations.
It may be 1'X10-9 mol/l, preferably lX
l0-'~lXl0-. ``mol/1, specifically, for example, about 6.75×1 per 100 g of phosphate buffer
It is sufficient to use approximately 0-' molar concentration, and this concentration is the molecular weight equivalent concentration (w/w) of polylysine, which is 0.015% in the case of polylysine molecular weight of 220,000, 0.00375% in the case of 55,000, and 0.00067 in the case of 8,000. %
corresponds to The molecular weight of polylysine may be that of a general commercially available product, for example, from 1,000 to 500,000.

Examples of the present invention will be given below as illustrations.

Example 1 (1) To prepare a forest material emulsion, various triglycerides (vanasate 800: carbon number of saturated fatty acid chain 8.1000:
Carbon number 10.1200: Carbon number 12.1400: Carbon number 14 and 1600: Carbon number 16, Nippon Oil & Fats@), purified egg yolk lecithin as an emulsifier (Asahi Kasei Kogyo)
), glycerin (Wako Pure Chemical Industries, Ltd.) was used as an isotonic agent, and palmitic acid (NOF@) was used as an emulsification aid. Using indomethacin (Wako Pure Chemical Industries, Ltd.) as a marker substance,
α-D-polylysine (Sigma Kagaku ■) was used to coat the surface of the emulsion particles.

Phosphate buffer solutions include sodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride (all from Wako Pure Chemical Industries, Ltd.
) to adjust the ionic strength to 0.154 and pH 7.4.
, 6, 8 and 6.1 were prepared.

2. Emulsion U-method lecithin 4.8g, glycerin log and palmitic acid 0.4g, and roughly indomethacin 0.2g?
40 g of dissolved triglyceride was mixed and dissolved with stirring for 15 minutes. Next, add the solution to 90°C.
Heated purified water was added to make the total amount 400 g. This mixture was heated to T using an autohomo mixer (Tokushu Kika Kogyo - Type B) at 90°C and a rotation speed of 1100.
Mechanical-secondary emulsification was performed for 20 minutes at 0 Orp. after that,
This emulsion was mixed with a homogenizer (WGAULIN 15M)
-8TA), 4500 psi.

Secondary emulsification was performed by bathing 10 times to prepare an O/W emulsion.

3. Drug release experiments from exfoliated fold emulsions were carried out using a suppository release tester (
It was carried out as follows using Toyama Sangyo ■). That is,
Pour 300ml of phosphate buffer adjusted to the specified pH into a three-necked bottle, and insert a filter (0,025μ) into it.
m) was attached. At this time, the temperature was kept constant at 37°C.

20 ml of the emulsion prepared in the above manner was used as a sample and discharged through the filter.

At this time, the release phase was stirred at a rotational speed of 75 rpm, and the rotational speed of the rotor in the emulsion was 10 rpm. The drug concentration in the release phase was determined by injecting 10 μβ of the released liquid sampled over time into a high performance liquid chromatography machine (LC4A, Shimadzu #1) with an absorbance of 260 nm and a column PR-3e.
lect B, and the flow rate was 1.5 ml/min.

At this time, the mobile phase was methanol:water:acetic acid-70730:
0.1, and the drug concentration was calculated by the absolute calibration curve method.

4. Experimental method A) Five types of emulsion samples were prepared using triglycerides with different fatty acid moieties in the oil phase.

In other words, the number of carbon atoms in saturated fatty acids is 8.10, 12.1
4 and 16 (hereinafter each k Ca, Coo, Co
zCZ and CI6). Furthermore, an emulsion using soybean oil as an oil phase and an aqueous drug solution were added, and a release experiment was conducted immediately after preparation for a total of seven samples. In addition, the pH of the released liquid was examined at three types, 7.4.6°7 and 6.1, assuming the absorption site in the blood and small intestine in a living body.

B) Preparation of Emulsion An emulsion was prepared by changing the amount of the oil phase to twice the amount of the above recipe. That is, 80g of C8 triglyceride
Emulsification was carried out in the same manner using 0.4 g of indomethacin, 9.6 g of lecithin, and 10 g of glycerin. Separately, each has a different molecular weight (M.

W=220000.55000 and 8800) P-L
ys was dissolved in a phosphate buffer of pH 6.7 (containing about 6.75 XlO mol per 100 g of phosphate buffer) to prepare solutions with the same molar concentration.

A certain amount of the emulsion was taken, and a P-L4s solution was added little by little into it until the volume ratio with the emulsion became 1=1, so that P-Lys was adsorbed on the surface of the emulsion. At this time, the mixed solution was continuously stirred, and after the addition of P-Lys, it was further stirred for 30 minutes and used as a sample.

Results A) Drug release characteristics from emulsions due to differences in oil phase Figure 1 shows the amount of indomethacin released from six emulsions with different oil phases and an aqueous drug solution as a control. This represents the result of measuring the pH of the release phase at 7.4, and it is clear that the release rate differs depending on the triglyceride used in the oil phase. For example, if released 8 hours after release, C8 will have 1. I X 10-5g/mj! (32%
), in C10, 9. OX 10-6g/ml (2
7%), CI□, 7. Ox 10-6g/m
+! (21%), at CI4, 2.0XIO-'g
/mff (11%), 1.5 x 1 in CI6
0-6g/m/! (4%), and as the number of carbon atoms in the fatty acid increased and the hydrophobicity of the oil phase increased, the drug release rate decreased.

In addition, the amount released from the drug solution (8) used as a control was 24
X I was 0-5 g/ml (70%), and drug release from the emulsion was completely suppressed due to the presence of the lentin interfacial film and the ease with which indomethacin and lipophilic drugs migrated into the oil phase. Seem.

Furthermore, soybean oil, which is typically used in the oil phase of fat emulsions, is characterized by its release amount or release pattern being located between C1□ and CI4, as shown in FIG.

B) Sustained release by modification of emulsion particles■P-Ls
Figure 2 shows the change over time in the amount released when oil droplets were coated with PLys having a molecular weight of 220,000, with drug release from an uncoated emulsion as a control. Note that C8 triglyceride, which had the highest release rate, was used for the oil phase of the emulsion. Obviously, P
The presence of the -Lys coating film suppressed the amount of drug released.

For example, after 8 hours, pH 7.4 is 1.1 × 10-5 g/mJ- + 4.6X
10-#'g/ml, 6.7 x 10-6g/ml at pH 6,7! -3.4
XlO-'g/mff, 3.4 X 10-''g/m1-1.7X at pH 6.1
Figure 2 shows release patterns from a 10' g/ml emulsion and a sustained release 0/W emulsion of the present invention.

It became.

As a result of examining the change in the amount of drug released when the molecular weight of P-Lys was set to 55,000 and 8,800, it was found that the amount released increased as the molecular weight decreased.

[Brief explanation of drawings]

Figure 1 shows the influence of fatty acids on the release of drugs from O/W emulsions, and Figure 2 shows the O/W procedure amendment June 26, 1991.

Claims (1)

[Claims] (1) A sustained release agent for O/W emulsion formulations containing polylysine as an active ingredient. (2), polylysine has a molecular weight of 1000 to 500000
The sustained release agent according to claim 1. (3) The sustained release agent according to claim 1, wherein the polylysine is D-form. (4) A sustained release emulsion preparation, which is an O/W emulsion preparation containing polylysine. (5) Polylysine has a molecular weight of 1000 to 500000
5. The formulation according to claim 4. (6) The preparation according to claim 4, wherein the polylysine is D-form. (7) The formulation according to claim 4, wherein the polylysine in the sustained release emulsion formulation is 1 x 10^-^5 to 1 x 10^-^9 mol/l. (8) The formulation according to claim 4, wherein the polylysine in the sustained release emulsion formulation is 1 x 10^-^6 to 1 x 10^-^8 mol/l. (9) The O/W emulsion formulation contains at least 1 oil or fat.
2 to 20 parts of emulsifier and appropriate amount of water per 00 parts
The formulation according to claim 4, which is an O/W emulsion formulation prepared with an oil content of 0% or less.