JP3074732B2 - Fat emulsion - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a preparation of a dihydropyridine compound which is a typical calcium antagonist used as a therapeutic agent for hypertension and angina. More specifically, the present invention relates to a pharmaceutical composition comprising a dihydropyridine compound, a simple lipid, a phospholipid and water.

BACKGROUND ART Calcium antagonists are excellent therapeutic agents for hypertension and angina, and dihydropyridine compounds, which are typical examples, have already been widely used in clinical practice.

However, it is difficult to formulate an injectable preparation of a dihydropyridine-based compound that is hardly soluble in water, and it has not been supplied clinically. In the production of injectable preparations of drugs that are poorly soluble in water, a technique of solubilizing polyoxyethylene hydrogenated castor oil (HCO-60), which is known as the only intravenously administrable surfactant, is known. .

However, this surfactant HCO-60 has recently been shown to cause anaphylactic shock and vascular irritation,
It is regarded as a problem as a pharmaceutical additive. Therefore, the clinical use of formulations using this technique is severely limited and has the disadvantage of not being able to provide sufficient drug therapy.

Therefore, development of a safe and effective injectable preparation containing a dihydropyridine compound has been eagerly desired.

The present inventors have formulated a dihydropyridine compound that is hardly soluble in water without containing a surfactant such as harmful polyoxyethylene hydrogenated castor oil (HCO-60), and added the molecular level of the dihydropyridine compound. As a result of continuing to study with the aim of providing a dosage form excellent in drug transferability to the site of action without affecting the pharmacological mechanism of action itself, we finally succeeded in completing the present invention It is.

Usually, the administered drug moves and distributes in the living body due to the inherent properties of the drug molecule. Then, it reaches the site of action and develops its medicinal effect. At this time, it is preferable that the drug is concentrated only at a site necessary for the onset of the drug effect, but generally, the drug is distributed throughout the body, and the drug moves to an unnecessary site. Sometimes this causes side effects. Thus, the importance and need to improve the pharmacokinetics of a drug arises.

In view of the above circumstances, the present inventors have made it possible to efficiently transfer a drug into tissues without affecting the pharmacological action itself of the drug, maintain the blood concentration of the drug, and Can reduce the amount of drug administered
As a result of continuing to study a new formulation of a safe and more effective dihydropyridine compound without using harmful additives,
Finally, the present invention has been successfully completed.

DISCLOSURE OF THE INVENTION The gist of the present invention is to limit the composition ratio of each component of simple lipid, phospholipid and water in producing a fat emulsion containing a dihydropyridine compound as a main component,
The reason is that the average particle diameter of the fat emulsion particles is set to a stable value of less than 100 nm.

In the present invention, the content of the dihydropyridine compound is 0.001 to 10% (w / v) based on the whole fat emulsion. Dihydropyridine-based compounds that are hardly soluble in water are preferred.

Representative examples include, for example, nifedipine, methyl
2,6-dimethyl-4- (2-nitrophenyl) -5
(2-oxo-1,3,2-dioxaphospholinan-2-yl) -1,4-dihydropyridine-3-carboxylate and the like.

In the present invention, the simple lipid is contained in an amount of 0.5 to 30% (w / v) based on the whole fat emulsion.

In the present invention, the phospholipid is contained in a weight ratio of 0.5 to 2 times the simple lipid.

Due to this, in a small amount, the incorporation of coarse particles is inevitable, and the average particle size of the stable emulsion particles containing the drug is 100 n.
Fat emulsion less than m cannot be obtained. When a larger amount of phospholipid is used, liposome particles cannot be avoided, and a uniform fat emulsion cannot be obtained.

Water, which is a component of the present invention, is contained in an appropriate amount.

The present invention has revealed for the first time that a stable micronized fat emulsion can be obtained by these components and that this is a pharmaceutical composition having extremely excellent characteristics and can be used as a preparation of a novel poorly soluble dihydropyridine compound. became.

Fat emulsion of the present invention, the average particle size of the emulsion particles is 100 nm
Is less than. The fat emulsion of the present invention does not contain emulsion particles of 1 μ or more. The fat emulsions of the invention are very fine and stable.

Since the emulsion particles of the fat emulsion of the present invention have an affinity for blood vessels and the like, a drug having an effect on the circulatory and vascular systems, such as a dihydropyridine compound, can be efficiently transferred to the site of action.

Emulsion particles having a size of about 100 nm or less can prevent the drug from being taken up by the non-specific reticuloendothelial system and have the effect of keeping the blood concentration of the drug high.

According to the present invention, since the dihydropyridine-based compound is present in the oil droplets of lipids and is present in a state of being shielded from the surrounding environment, enzymatic or non-enzymatic degradation can be suppressed, and after administration, Can also improve drug stability.

In addition, since the fat emulsion of the present invention has turbidity, the light stability of a dihydropyridine-based compound unstable to light can be improved. This can be said to be one of the effects of the present invention.

Examples of the simple lipid according to the present invention include refined soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, triolein, trilinolein, tripalmitin, tristearin, trimyristin, triarachidonin and the like. And neutral lipids. Further, sterol derivatives such as cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate and cholesteryl arachidate can be mentioned.

Neutral lipids are relatively easily degraded by various lipases present in the vascular endothelium, etc., whereas cholesterol derivatives are less susceptible to degradation by these enzymes and further increase their stability in the body. Preferred as a constituent.

Examples of the phospholipid according to the present invention include phospholipids derived from egg yolk, soybean, cow, pig, and the like, and phospholipids obtained in a purely synthetic or semi-synthetic manner. That is,
Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol and the like. Further, for example, egg yolk phosphatidylcholine, soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylglycerol and the like can be mentioned. These hydrogenated products can also be used. Among them, a preferable representative example is purified egg yolk lecithin.

In addition, stearylamine, dicetyl phosphate, phosphatidic acid,
Charged lipids such as phosphatidylglycerol can also be used.

In the production of the fat emulsion of the present invention, various conventional emulsion production methods can be applied as they are. For example, a method is generally used in which all components including a drug are sufficiently miniaturized and formed by a pressure-jet type homogenizer such as a Manton-Gaurin type, a microfluidizer, an ultrasonic homogenizer, or the like.

At this time, physiologically acceptable sterols, fatty acids or their derivatives can be added as generally known emulsifying aids or stabilizers. Representative examples of these include cholesterol and oleic acid.

The shape and particle size of the fat emulsion of the present invention can be easily confirmed by an electron microscope, a light scattering type particle size analyzer, filtration with a membrane filter, and the like.

The fat emulsion of the present invention may contain, for example, additives and auxiliary substances generally used for injections, in addition to the main component of the present invention. Suitable examples thereof include antioxidants, preservatives, stabilizers, tonicity agents, buffers and the like. The required and optimal amounts of these additives, auxiliary substances, etc. can be varied according to the purpose.

The fat emulsion of the present invention obtained as described above is sterilized as necessary (eg, sterilized by filtration or autoclaved),
It can be sealed in an ampoule with nitrogen gas.
Also, it can be freeze-dried as needed. The lyophilized fat emulsion of the present invention can be reconstituted by adding an appropriate solution.

The preparation comprising the fat emulsion of the present invention is generally administered intravenously to humans or various animals for the purpose of treating or preventing hypertension, angina, etc., or controlling blood pressure.

In this case, it is necessary to sufficiently control the grain size of the emulsion grains. This is because, when particles of 1 μm or more are generally mixed, various toxicities are known.

Also, the preparation comprising the fat emulsion of the present invention can be administered into the artery, intramuscularly, intrathecally, subcutaneously, etc., if necessary, as with other injections. Further, the fat emulsion of the present invention can also be formulated and used as eye drops, nasal drops, oral preparations, inhalants, bladder injections, suppositories, ointments and the like. Also in this case, pharmaceutically acceptable bases, additives such as excipients and the like can be contained in the fat emulsion of the present invention in addition to the main component of the present invention.

The dosage of the preparation comprising the fat emulsion of the present invention varies depending on the route of administration, dosage form, symptoms and purpose, but generally 1 to 1000 ml / time of the emulsion is preferable. The dose of the dihydropyridine compound is generally
0.1-100mg / time is good.

According to the present invention, the clinical utility value of a dihydropyridine compound can be significantly increased.

The effect of the present invention overcomes the problem that an injection of a suitable injectable poorly soluble dihydropyridine compound could not be produced in the past, and without affecting the pharmacological action itself of the drug, an efficient tissue A new class of safe and more effective dihydropyridine compounds that can transfer into the body, maintain the blood concentration of the drug, reduce the required drug dosage, and use no harmful additives. It can be summarized as the achievement of formulation. These effects are achieved for the first time by the present invention.

Since the constituents of the fat emulsion of the present invention are mainly composed of medically acceptable lipids which have been conventionally used for medical purposes in medical practice, they can be used extremely safely. This is also one of the important effects of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail by way of examples relating to production of a fat emulsion of the present invention, but it is apparent that the present invention is not limited to these. .

Production Example 1 After mixing and dissolving 3 mg of nifedipine, 0.5 g of purified soybean oil and 0.5 g of purified egg yolk lecithin in 100 ml of a mixed solution of chloroform / methanol (1/1, v / v), the solvent was completely removed under reduced pressure using a rotary evaporator. I do. To this, 8 ml of a 0.24 M glycerin aqueous solution is added and stirred with a homogenizer to obtain a coarse emulsion. After adding a 0.24M glycerin aqueous solution to make the volume to 10 ml, the mixture is cooled with ice and an ultrasonic homogenizer (Branson
The mixture was emulsified with a model 185) for 60 minutes to obtain a very fine fat emulsion containing nifedipine.

Production Example 2 Nifedipine 20 mg, purified soybean oil 0.25 g, and purified egg yolk lecithin 0.25 g were mixed with chloroform / methanol (1/1, v / v).
v) After mixing and dissolving in 100 ml of the mixed solution, the solvent is completely removed under reduced pressure using a rotary evaporator. To this, 8 ml of isotonic phosphate buffer is added and stirred with a homogenizer to obtain a coarse emulsion. After adding an isotonic phosphate buffer and making the volume to 10 ml,
Under ice cooling, an ultrasonic homogenizer (Branson model 18
The mixture was emulsified for 60 minutes in 5) to obtain a fat emulsion containing extremely fine nifedipine.

Production Example 3 2 g of nifedipine, 20 g of purified soybean oil, and 30 g of purified egg yolk lecithin are heated and mixed at about 60 ° C., and 100 ml of a 0.24 M glycerin aqueous solution is added thereto, followed by stirring with a homomixer to obtain a coarse emulsion. The coarse emulsion was emulsified under high pressure using a microfluidizer to obtain a fat emulsion containing extremely fine nifedipine.

Production Example 4 Nifedipine 1 mg, cholesteryl oleate 0.5 g, and purified egg yolk lecithin 0.5 g were mixed with chloroform / methanol (1/1).
1, v / v) After mixing and dissolving in 100 ml of the mixture, the solvent is completely removed under reduced pressure using a rotary evaporator. to this,
8 ml of a 0.24 M glycerin aqueous solution is added, and the mixture is stirred with a homogenizer to obtain a coarse emulsion. Add 0.24M glycerin aqueous solution and add 10m
l to an ultrasonic homogenizer (Branson
The mixture was emulsified with a model 185) for 60 minutes to obtain a very fine fat emulsion containing nifedipine.

Production Example 5 Nifedipine 3 mg, purified soybean oil 0.5 g, purified egg yolk lecithin 0.4 g, dimyristoyl phosphatidylglycerol 0.1 g chloroform / methanol (1/1, v / v) mixed solution 10
After mixing and dissolving in 0 ml, the solvent is completely removed under reduced pressure using a rotary evaporator. To this, 8 ml of 9% lactose aqueous solution is added and stirred with a homogenizer to obtain a coarse emulsion. After adding 9% lactose aqueous solution to make the volume to 10 ml,
60 with an ultrasonic homogenizer (Branson model 185)
After emulsification for one minute, an extremely fine fat emulsion containing nifedipine was obtained.

Production Example 6 Nifedipine 5 mg, purified soybean oil 0.5 g, hydrogenated egg yolk lecithin 0.4 g, and cholesterol 0.1 g were mixed with chloroform /
After mixing and dissolving in 100 ml of a mixed solution of methanol (1/1, v / v), the solvent is completely removed under reduced pressure using a rotary evaporator. To this, 8 ml of 9% lactose aqueous solution is added and stirred with a homogenizer to obtain a coarse emulsion. After adding a 9% lactose aqueous solution to make the volume to 10 ml, the mixture was emulsified with an ultrasonic homogenizer (Branson model 185) for 60 minutes to obtain an extremely fine fat emulsion containing nifedipine.

Production Example 7 Methyl 2,6-dimethyl-4- (2-nitrophenyl) -5- (2-oxo-1,3,2-dioxaphospholinan-2-yl) -1,4-dihydropyridine-3- 3 mg of carboxylate, 0.5 g of purified soybean oil, and 0.5 g of purified egg yolk lecithin are mixed with chloroform / methanol (1/1, v / v) 10
After mixing and dissolving in 0 ml, the solvent is completely removed under reduced pressure using a rotary evaporator. To this, 8 ml of a 0.24 M glycerin aqueous solution is added and stirred with a homogenizer to obtain a coarse emulsion. After adding a 0.24 M glycerin aqueous solution to make the volume to 10 ml, the mixture was emulsified with an ultrasonic homogenizer (Branson model 185) for 60 minutes under ice cooling to obtain an extremely fine fat emulsion.

Production Example 8 0.5 g of albumin was added to the dihydropyridine-based compound-containing fat emulsion obtained in Production Examples 1, 4, 5, and 7, followed by freeze-drying to obtain a dry preparation.

(Measurement of Particle Diameter) The particle diameter was evaluated using a dynamic light scattering particle diameter measuring apparatus using laser light.

As a result, the fat emulsion of the present invention produced according to Production Examples 2 and 7 had an average particle size of about 20 to about 100 nm. Also, it did not contain particles of 1 μ or more.

It is clear that the fat emulsions according to the invention consist of very fine, uniform emulsion grains. In addition, when administered intravenously, it does not contain particles of 1μ or more that pose a toxicity problem.
It is clear that effective and safe drug therapy is achieved.

INDUSTRIAL APPLICABILITY As described above, the present invention is useful in the pharmaceutical industry because a dihydropyridine compound, which is a therapeutic agent for hypertension, angina, etc., can be safely administered as an injection in an effective amount.

Continuation of the front page (56) References JP-A-60-115517 (JP, A) JP-A-1-143826 (JP, A) JP-A-1-249716 (JP, A) JP-A-64-16716 (JP) , A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/4422 A61K 9/107 A61K 9/127 A61K 9/14 A61K 31/675 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] The present invention relates to (a) 0.001 to 10% (w / v) of a total of dihydropyridine compounds, (b) 0.5 to 30% (w / v) of a simple lipid, and (c) a simple lipid. A lipid emulsion containing 0.5 to 2 times (weight ratio) phospholipids and (d) an appropriate amount of water, wherein the fat emulsion particles contain dihydropyridine-based compound-refined soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn Oil, peanut oil, and at least one simple lipid selected from the group consisting of safflower oil, and a phospholipid,
A fat emulsion having an average particle size of less than 40 nm, or a freeze-dried preparation thereof. 2. The method according to claim 1, wherein the phospholipid is phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine,
The fat emulsion according to claim 1, which is phosphatidylinositol or phosphatidylglycerol, or a freeze-dried preparation thereof. 3. The fat emulsion according to claim 1, wherein the simple lipid is purified soybean oil and the phospholipid is purified egg yolk lecithin, or a freeze-dried preparation thereof. 4. The fat emulsion according to claim 1, further comprising at least one selected from the group consisting of stearylamine, dicetyl phosphate, phosphatidic acid, and phosphatidylglycerol, or any one of them. Lyophilized formulation. 5. The method of claim 1, wherein the dihydropyridine compound is nifedipine or methyl 2,6-dimethyl-4- (2-nitrophenyl) -5- (2-oxo-1,3,2-dioxaphospholinan-2-yl. ) -1,4-Dihydropyridine-3
The fat emulsion according to any one of claims 1 to 4, which is a carboxylate, or a freeze-dried preparation of any of the fat emulsion. 6. The fat emulsion according to claim 1, wherein the preparation is in the form of an injection, an eye drop, a nasal drop, an orally administered drug, an inhalant, a bladder injection, a suppository, or an ointment. Or a lyophilized formulation of any of them.