JP2001151702A - Parenteral pharmaceutical composition containing phospholipid affinitive medicament - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a parenteral medicinal composition capable of being safely used in a pharmaceutical preparation for injection or the like, without diluting the concentration of such a medicament that is difficult to be administered because of causing vasculopathy. SOLUTION: This parenteral medicinal composition contains an amphipathic medicament having an affinity for phospholipid and an oil-in-water type fat emulsion, wherein the amphiphatic medicament which is dissolved in water in such a concentration as to be clinically applicable migrates at least partially to a phospholipid layer of the fat emulsion so that the concentration of the medicament dissolved in the water phase of the fat emulsion decreases.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a parenteral drug composition in which at least a part of an amphipathic drug having an affinity for phospholipids is present in a phospholipid layer of a fat emulsion. The present invention relates to a parenteral drug composition characterized by reducing the local harmfulness of origin, a method for producing the same, and a pharmaceutical kit which can be mixed at the time of use.

[0002]

2. Description of the Related Art JP-A-63-48214 and JP-B-1-57094 describe that a drug is contained in a fat emulsion to reduce local impairment upon administration. The drug is a drug that is hardly soluble in water, is soluble in water at a clinically usable concentration, and has clearly different physical properties from the drug used in the present invention described below, which has affinity for phospholipids. Patent No. 2653245 also describes that a drug is contained in a fat emulsion. However, the drug is a poorly water-soluble drug, and as described above, the physical properties of the drug used in the present invention described below. Obviously different.

[0003]

A parenteral drug, especially an injection, is a poorly absorbable drug which is difficult to obtain an effective amount as a blood concentration when compared with a drug administered orally, and its stability in the digestive tract. It is effective as a dosage form for low-drug drugs and drugs that require immediate action. However, as a problem often observed in injections, disability caused by the injection locally at the site of administration (hereinafter sometimes referred to as “local impairment”).
Is involved. Such local impairment is mainly caused by a pH or osmotic pressure which is out of an acceptable range of a living body in an injection, and is caused by a prescription component such as a main drug or an additive. Therefore, as long as the stability of the main drug is not impaired, the pH of the injection is adjusted to near neutrality and the osmotic pressure is adjusted to approach isotonicity, and additives having high safety are selected.

[0004] On the other hand, as for the reduction of local harm caused by the main drug at the time of drug administration, there is currently no effective means applied to injections. For example, a method is known in which the active drug concentration is reduced to a concentration acceptable for the tissue at the site of administration. Nevertheless, it is said that the merchantability is low. In addition, since this method cannot be generally applied to a drug that causes instability due to a decrease in concentration, it is generally difficult to formulate an injection.

Accordingly, there has been a demand for a parenteral drug composition which can be safely used for injection preparations without reducing the concentration of a drug which is difficult to administer due to vascular damage.

[0006] Focusing on the fact that many drugs that damage biological tissues have an affinity for biological membranes, ie, phospholipids in biological membranes, and as a result of intensive research on compounds and drugs having such properties, It has been found that in the case of a drug having such properties, in the presence of a fat emulsion, the drug partitions into the phospholipid layer, and the concentration of the free drug in the aqueous solution decreases. And such a phenomenon is useful in reducing local damage caused by a parenteral drug such as an injection, and furthermore, a drug having an affinity for the present phospholipid is a fat emulsion completed at the time of use. It has been found that partitioning to the phospholipid layer is achieved only by mixing, and the present invention has been completed.

[0007]

According to the present invention, an amphipathic drug having an affinity for phospholipids (hereinafter sometimes simply referred to as "amphiphilic drug") and an oil-in-water fat emulsion are provided. In a parenteral drug containing, the drug soluble in water at a clinically usable concentration is at least partially incorporated into a phospholipid layer in a fat emulsion, so that the drug enters the aqueous phase in the fat emulsion. A parenteral drug composition characterized by a reduced dissolution concentration, a method for producing the same, and a parenteral drug containing an amphiphilic drug having an affinity for phospholipids and an oil-in-water fat emulsion, The drug which dissolves in water at a usable concentration is at least partially incorporated into the phospholipid layer in the fat emulsion, and the dissolution concentration of the drug in the aqueous phase in the fat emulsion is reduced. Provide a way to reduce .

Further, the present parenteral drug composition can mix a drug and a fat emulsion at the time of use, and can be applied to a drug whose long-term stability cannot be maintained in a fat emulsion. Drug, if necessary, solubilizer, tonicity agent,
A pharmaceutical kit comprising a freeze-dried composition or a dry powder composition containing a pH regulator and an antioxidant and an oil-in-water fat emulsion is provided.

The terms used in the present specification are described below.

The “amphiphilic drug” in the present invention is:
A drug that has an affinity for phospholipids and that has a clinically effective drug-soluble drug in water, and is distributed to phospholipids more than oil components that can be used in fat emulsions. (Hereinafter, sometimes referred to as “drug used in the present invention”). Such amphiphilic drugs include, for example, sodium sulfobromophthalein, chlorpromazine hydrochloride, polymyxin B, and the like, and any drug may be used as long as it has the properties described above. Applies to drugs that cause disability. When the drug used in the present invention is present together with a fat emulsion, usually about 30% by weight or more of the drug binds to the phospholipid in the fat emulsion. Preferably about 4
Drugs that bind to phospholipids in an amount of 0% by weight or more, more preferably about 50% by weight or more, and particularly about 80% by weight or more are particularly preferred. Further, the drug used in the present invention is preferably one that is hardly distributed to the oil component described later in the fat emulsion. For example, the amount distributed to the oil component is up to about 10% by weight of the drug.
And those that hardly partition to the oil component are more preferred.

The fat emulsion means a mixture of at least a component comprising a phospholipid as a constituent and an oil component, and the constituent phospholipids include phosphatidylcholine, phosphatidylserine derived from soybean or egg yolk, Examples thereof include phosphatidylglycerin, phosphatidylinositol, and phosphatidylethanolamine. A mixture of two or more of these and a hydrogenated product of these compounds can also be used. As the oil component, high-purity plant-derived oils, such as soybean oil, corn oil, sesame oil,
Safflower oil, cottonseed oil, coconut oil and the like can be used. In addition, the fat emulsion may contain an emulsifying aid and a tonicity agent. The fat emulsion defined in the present invention is usually 0.1%.
It contains from about 30% by weight of an oil component and from 0.002% to about 20% by weight of a phospholipid.

When a fat emulsion and a drug are mixed, generally, the surface of the fat emulsion is covered with a phospholipid, and fat emulsion particles having a structure in which an oil component is disposed therein are scattered, and are present.
The water phase occupies the portion around the fat emulsion particles. Then, a part of the amphiphilic drug is incorporated into the fat emulsion particles, and a state is formed in which the remaining drug is present in the aqueous phase. The average particle size of the fat emulsion particles is about 1 μm or less,
It is preferably from 0.01 to 0.5 μm, more preferably from 0.05 to about 0.25 μm.

The parenteral composition of the present invention may further contain an emulsifying aid, or may contain an emulsifying aid as a fat emulsion as described above. As the emulsifying aid, surfactants and fatty acid salts and cholesterol that can be used as pharmaceuticals can be used. Particularly, surfactants to be added to injectable preparations include low-toxin nonionic surfactants. It is desirable to use, for example, polysorbate 80, polysorbate 20, polyoxyethylene / polyoxypropylene copolymer (Pluronic F-
68: manufactured by Asahi Denka). These emulsifying aids can be used alone or in combination of two or more.

The parenteral composition of the present invention may further comprise a tonicity agent or may comprise a tonicity agent as a fat emulsion as described above. As the tonicity agent, for example,
Glycerol, glucose, mannitol, sorbitol and the like can be mentioned.

The parenteral drug composition of the present invention may further contain, if necessary, a pH regulator, a drug and / or an antioxidant for stabilizing a fat emulsion. Examples of the pH adjuster include organic acids such as lactic acid, citric acid, and phosphoric acid or salts thereof, sodium hydroxide, and hydrochloric acid. As antioxidants, for example, tocopherol,
Although sodium hydrogen sulfite is mentioned, oxidation can be prevented by performing nitrogen gas substitution.

The parenteral composition of the present invention is characterized in that, when an amphipathic drug and a fat emulsion are mixed at the time of use, a small amount of a solubilizing agent which does not affect the fat emulsion after mixing with the amphipathic drug. Can be added. Examples of the solubilizing agent include ethanol, propylene glycol, glycerol, polyethylene glycol 300, polyethylene glycol 400, and the like, and the surfactants described above.

The present invention relates to a parenteral drug comprising an amphipathic drug and a fat emulsion, wherein a drug having a phospholipid affinity is distributed to an oil component in the fat emulsion. As a result, the drug is preferably at least partially incorporated into the phospholipid layer with little distribution, thereby achieving a good distribution of the drug to each component in the fat emulsion. As a result, by reducing the concentration of the drug dissolved in the aqueous phase in the fat emulsion as compared to an aqueous solution at a concentration at which the drug exerts clinical efficacy, by allowing the drug to be present in the phospholipid in the fat emulsion, The entire clinically necessary dose can be ensured in the fat emulsion, which can reduce local damage during drug administration, increase drug stability, improve drug efficacy and reduce drug toxicity. And

Hereinafter, a method for producing the parenteral pharmaceutical composition of the present invention will be described.

The parenteral pharmaceutical composition of the present invention comprises at least a component comprising a phospholipid as a component and an oil component, and if necessary, an emulsifier, an isotonic agent, a pH adjuster, and an antioxidant. In addition, these mixtures are mixed with a BEEI high-pressure homogenizer,
After making an oil-in-water fat emulsion by making it sufficiently fine by using a Menton-Gaurin homogenizer, a microhomogenizer (microfluidizer), an ultrasonic homogenizer, etc., an amphiphilic drug is added to the aqueous phase of the fat emulsion and mixed. Can be manufactured.

The parenteral drug composition obtained as described above can be used after freeze-drying.

The parenteral drug composition of the present invention can be prepared by separately preparing a fat emulsion, storing it separately from the amphipathic drug, and mixing the two before use. At this time, the form of the drug may be a lyophilized preparation, a subdivided powder, or a solution. If necessary, the above-mentioned tonicity agent, stabilizer, solubilizing agent and the like can be added to these in advance.

The parenteral pharmaceutical composition of the present invention is generally used as an injection, and is administered intravenously, intraarterially, intramuscularly or subcutaneously to the body. Administration is the preferred mode of administration. It can also be used as another parenteral administration form, for example, suppositories and patches.

Hereinafter, the present invention will be described in more detail and with specific examples, but the present invention is not limited thereto.

Example 1 : Egg yolk lecithin 12 g, soybean oil 100
g, 25 g of glycerol and 400 mL of water for injection were pre-emulsified by a dual-feed system using a high-pressure homogenizer DeBee2000 (manufactured by BEEI) to obtain an emulsion. This emulsion was subjected to high-pressure emulsification by a reverse method using a high-pressure homogenizer DeBee2000 to obtain a fat emulsion having a particle size of 0.2 μm. Next, 25 g of sodium sulfobromophthalein (hereinafter referred to as “BSP”) was dissolved in 450 mL of water for injection, and this solution was added to the fat emulsion and mixed. Hydrochloric acid was added thereto to adjust the pH to 6, and then water for injection was added to make the total volume 1000 mL. Finally, sterilization by filtration was performed to obtain a parenteral drug composition having a final component concentration of 25 mg / mL BSP and a 10% fat emulsion.

Example 2 Chlorpromazine hydrochloride (hereinafter, referred to as chlorpromazine hydrochloride)
Called "CPZ". 5) 5 g was dissolved in 450 mL of water for injection, and this solution was added to the fat emulsion prepared by the method described in Example 1 and mixed. To this was added sodium hydroxide to adjust the pH to 6, and then water for injection was added to make the total volume 1000 mL. Finally, sterilization by filtration was performed to obtain a parenteral drug composition having a final component concentration of 5 mg / mL CPZ and a 10% fat emulsion.

Example 3 After 5 g of BSP was dissolved in 90 mL of water for injection, 0.5 g of phosphoric acid and an appropriate amount of sodium hydroxide were added thereto to adjust the pH.
Was adjusted to 6, and water for injection was further added to bring the total volume to 100 mL. Finally, heat sterilization was performed to obtain a drug solution.

Separately, 24 g of egg yolk lecithin, 200 g of soybean oil, 50 g of glycerol and 700 mL of water for injection were added to a high-pressure homogenizer.
Pre-emulsification by DeBee2000 dual feed method,
An emulsion was used. Water for injection was added to this emulsion to make the total volume 1000 mL, followed by high-pressure emulsification by a reverse method using a high-pressure homogenizer DeBee2000 to obtain a fat emulsion having a particle size of 0.2 μm. Lastly, sterilize by filtration and use 20%
It was a fat emulsion.

At the time of use, 3 mL of the drug solution and 3 mL of the fat emulsion are mixed, and the final component concentration is 25 mg / mL BSP, pH of 10% fat emulsion.
6 parenteral drug compositions were obtained.

Example 4 1 g of CPZ was dissolved in 90 mL of water for injection, and then 0.5 g of phosphoric acid and an appropriate amount of sodium hydroxide were added to adjust the pH.
Was adjusted to 6.5, and water for injection was further added to make the total volume 100 mL. Finally, heat sterilization was performed to obtain a drug solution.

Separately, according to the method described in Example 3 above, a 20% fat emulsion for mixing at the time of use was prepared. Drug solution 2.5 before use
Mix 2.5 mL of the fat emulsion and 2.5 mL of the final component to give a final concentration of 5 mg / mL.
A parenteral drug composition at pH 6 as a CPZ, 10% fat emulsion was obtained.

Example 5 : 2.5 g of BSP and 5 g of mannitol
Was dissolved in 90 mL of water for injection, 0.5 g of phosphoric acid and an appropriate amount of sodium hydroxide were added to adjust the pH to 6, and water for injection was further added to bring the total volume to 100 mL. Subsequently, heat sterilization was performed to obtain a drug solution. 6 mL of this drug solution was dispensed into vials and freeze-dried to obtain a freeze-dried preparation.

Separately, according to the method described in Example 1 above, 10
% Fat emulsion was prepared. When used, 6 mL for freeze-dried drug product
Of the final component concentration of 25 mg / mL BSP, 10%
A parenteral drug composition of pH 6 as a fat emulsion was obtained.

Example 6 : 0.5 g of CPZ and 5 g of mannitol
Was dissolved in 90 mL of water for injection, 0.5 g of phosphoric acid and an appropriate amount of sodium hydroxide were added to adjust the pH to 6, and water for injection was further added to bring the total volume to 100 mL. Subsequently, heat sterilization was performed to obtain a drug solution. 5 mL of this drug solution was dispensed into vials and freeze-dried to obtain a freeze-dried preparation.

Separately, according to the method described in Example 1 above,
% Fat emulsion was prepared. When used, 5 mL for lyophilized drug
Fat emulsion, and the final component concentration is 5 mg / mL CPZ, 10%
A parenteral drug composition of pH 6 as a fat emulsion was obtained.

The free drug concentration (drug concentration in the aqueous phase) of each parenteral drug composition and the rate of incorporation into a fat emulsion are shown below.

Measurement of Free Drug Concentration The free drug concentration of each parenteral drug composition was determined by quantifying the drug in the aqueous phase by ultrafiltration. Examples 1 and 2 are the values at the time when the drug was dissolved, and Examples 3, 4, 5, and 6 are the values immediately after mixing the drug and the fat emulsion.

Calculation of incorporation rate into fat emulsion The amount of drug incorporated into the fat emulsion was determined from the amount of free drug,
It is shown as a percentage of the total amount of drug. Table 1 shows the results of the free drug concentration and the uptake rate.

[Table 1]

According to Table 1, the free drug concentration (drug concentration in the aqueous phase) of each drug in the presence of the fat emulsion is reduced by 50% or more in BSP and 90% or more in CPZ as compared with the case of the aqueous solution alone. I was

Therefore, for the phospholipid egg yolk lecithin and soybean oil, which are the main components of the fat emulsion, each was used as the oil phase, and the oil-water distribution test using water as the aqueous phase was carried out using BSP or CPZ.
Table 2 shows the results of the incorporation rate into the oil phase.

[Table 2]

As is clear from Table 2 above, BSP and CPZ
Was found to hardly partition to soybean oil, but to partition to the phospholipid egg yolk lecithin. Therefore, BSP and C
It is strongly suggested that PZ is present in the phospholipid layer in the fat emulsion in the presence of the fat emulsion. Although the uptake rates of the fat emulsion and the phospholipid alone in Table 2 seemed to be different from each other due to the difference in particle size, the uptake rates of the fat emulsion and the phospholipid alone were similar, and the soybean oil in Table 2 was similar. Since it is hardly incorporated into the lipid emulsion, the incorporation rate into the fat emulsion can be read as the binding rate to the phospholipid.

The following is an experimental example relating to the venous injury of the parenteral pharmaceutical composition of the present invention.

Intravenous Local Toxicity Test The fat emulsion ( pH 6) used in Example 1 and the aqueous solution containing BSP (p
H6), 1 mL each of the CPZ-containing aqueous solution (pH 6) and the parenteral drug composition (pH 6) of Examples 1 and 2 were each used in Japanese white male male rabbits [3 animals per group (excluding sample No. 1), A body weight of 2.5 to 3 kg] was continuously administered once a day for 5 days at an infusion rate of 1 mL / min, and the area around the auricular vein was observed. The degree of venous damage was evaluated by observing the vein and surrounding vein every 24 hours of each administration, and by the presence or absence of thrombus and the size of erythema. The criteria for venous dysfunction are as follows. Table 3 shows the results.

Thrombus: presence or absence in auricular vein Erythema:-equivalent to control ± erythema several cm square at administration site + about 1/4 of auricle ++ about half of auricle +++ More than half of auricle

When a thrombus occurred in the vein, the subsequent administration was stopped. Physiological saline was used as a control for the test solution.

[0045]

[Table 3]

As is clear from Table 3, in the parenteral drug containing CPZ and BSP containing no fat emulsion (samples No. 2 and No. 3), did erythema develop in at least half of the pinna of the tested rabbits? Alternatively, the parenteral drug composition of Examples 1 and 2 containing a fat emulsion (sample No. 4, N
o.5) significantly reduced venous dysfunction.

[0047]

The parenteral pharmaceutical composition of the present invention can be used for parenteral administration caused by an amphipathic drug having an affinity for phospholipids by employing a fat emulsion as a drug carrier. The present invention reduces local impairment, particularly venous impairment during injection administration, and enables administration of a drug having such properties, which has heretofore been difficult to administer due to vascular impairment. Further, the parenteral drug composition of the present invention has an advantage that by separately producing the drug-containing composition and the fat emulsion, storage is easy and the stability of the drug can be maintained for a long period of time. In addition, by using the parenteral drug composition of the present invention, the stability of the drug used in the present invention can be increased by incorporating the drug into phospholipids in a fat emulsion, and further, improving the drug efficacy of the drug and Toxicity reduction is also possible.

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Claims (12)

[Claims] 1. A parenteral drug containing an amphipathic drug having an affinity for phospholipid and an oil-in-water fat emulsion, wherein the drug soluble in water at a clinically usable concentration is contained in the fat emulsion. A parenteral pharmaceutical composition characterized in that the concentration of the drug dissolved in the aqueous phase in the fat emulsion is reduced by at least partially incorporation into the phospholipid layer. 2. The parenteral pharmaceutical composition according to claim 1, wherein the amphiphilic drug is a drug that binds to phospholipids in a fat emulsion in an amount of 50% by weight or more. 3. A fat emulsion comprising soybean oil, corn oil, sesame oil,
The parenteral pharmaceutical composition according to claim 1 or 2, comprising at least one oil component selected from sunflower oil, cottonseed oil, and coconut oil, and at least one phospholipid. 4. The parenteral pharmaceutical composition according to any one of claims 1 to 3, wherein local toxicity is reduced upon administration. 5. The parenteral pharmaceutical composition according to claim 4, which is an injection. 6. The injection according to claim 5, wherein the local injury is venous local injury. 7. The parenteral drug composition according to any one of claims 1 to 6, wherein the amphiphilic drug and the fat emulsion are separately present, and the two are mixed and used at the time of use. object. 8. A lyophilized product or a powdered subdivided product by adding a solubilizing agent, an isotonic agent, a pH adjuster, and an antioxidant to an amphiphilic drug which is separately present, if necessary. The parenteral pharmaceutical composition according to claim 7, characterized in that: 9. A component having at least a phospholipid as a component and an oil component, and if necessary, an emulsifying aid, an isotonic agent, a pH adjuster, and an antioxidant are added thereto, and the mixture is subjected to a homogenizer. Production of a parenteral drug composition characterized by sufficiently finely forming an oil-in-water fat emulsion, followed by adding an amphiphilic drug having an affinity for phospholipid to an aqueous phase of the fat emulsion and mixing. Law. 10. A composition obtained by adding a solubilizing agent, an isotonic agent, a pH adjusting agent, and an antioxidant to an amphipathic drug having an affinity for phospholipids, if necessary, and freeze-drying the composition. Drugs,
A pharmaceutical kit comprising a powdery composition to which each agent is added as needed, a composition selected from the drug, a liquid composition to which each agent is added as needed, and an oil-in-water fat emulsion. 11. A freeze-dried product or a powdered product obtained by adding a solubilizing agent, an isotonic agent, a pH adjusting agent, and an antioxidant to an amphiphilic drug having an affinity for phospholipids, if necessary. The composition for producing the parenteral drug composition according to claim 7 or 8, wherein 12. A parenteral drug containing an amphipathic drug having an affinity for phospholipid and an oil-in-water fat emulsion,
When the drug soluble in water at a clinically usable concentration is at least partially incorporated into the phospholipid layer in the fat emulsion and the concentration of the drug dissolved in the aqueous phase in the fat emulsion is reduced, the parenteral To reduce local impairment during targeted administration.