JPS63264517A - Drug composition - Google Patents

Abstract

PURPOSE:To obtain a novel drug composition effectively making various drugs such as anti-inflammatory drug or carcinostatic drug accumulate and retain at crisis site, having low toxicity and excellent medicinal effects with a small amount of administration, comprising a drug, phospholipid, a glycerylphosphoryl compound and water. CONSTITUTION:A composition comprising a drug, phospholipid, a glycerylphos phoryl compound shown by the formula [R1 is 16C or 18C alkyl; R2 is 1-3C alkyl; R3 is N(CH3)3, N(CH3)2 or NHCH3 or NH2] and water. A fat emulsion or liposome is especially preferable as the form of the drug composition. To be concrete, for example, in the case of the case of the fat emulsion, a fat- soluble drug is preferable as the drug and a vegetable oil, preferably soybean oil is used. First the vegetable oil is blended with the phospholipid, the drug, the compound shown by the formula and optionally an additive, heated homoge nized by a homogenizer to give a water-in-oil type dispersion, which is mixed with water, rehomogenized and converted into an oil-in-water type emulsion to give the aimed composition.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Application The present invention relates to a novel pharmaceutical composition. In detail, the additive is represented by the general formula (I) (where R is an alkyl group having 16 or 18 carbon atoms or an acyl group having 16 or 18 carbon atoms, R2 is an alkyl group having 1 to 3 carbon atoms, and R3 is an alkyl group having 1 to 3 carbon atoms. N (CH3)
3, N (CH3) 2 , NHCH3 or NH2).

(b) Prior Art Fat emulsions consisting of vegetable oil, phospholipids and water, and liposomes consisting of phospholipids and water have both been used as unique drug carriers.

The characteristics of these drug carriers are that they have a specific affinity for the site of disease, the reticuloendothelial system, especially phagocytic cells (macrophages, hepatocytes, etc.), and by being taken up by these cells, the effects of the drug are expressed. It is in.

That is, it has been proven that the drug is taken up and accumulated in areas where there are many phagocytic cells, such as inflammatory sites and cancer sites, and that the effect is expressed, and that the effect is sustained due to retention.

On the other hand, the glycerylphosphoryl derivative represented by the general formula (I) is also called platelet activating factor (PAF), and is a chemical mediator that activates phagocytic cells such as platelets and macrophages in minute amounts (5 μg/kg, rat). It is one of a kind. This glycerylphosphoryl derivative (I) is known to have a high binding ability and phagocytosis with phagocytic cells.

This glycerylphosphoryl compound (I) is widely distributed in mammalian cells, but is not contained in natural phospholipids (eg, egg yolk phospholipids, soybean phospholipids, etc.).

(c) Problems to be Solved by the Invention Therefore, the present inventors sought to develop an even better drug carrier (as a result of various studies, a pharmaceutical composition comprising a drug carrier such as a fat emulsion or liposome, Glycerylphosphoryl compound (I) as an additive
It was discovered that the accumulation of the drug at the site of onset of symptoms was improved by adding , and the present invention was completed based on this finding.

(d) Means for Solving the Problems The drug of the present invention is not particularly limited, and a wide variety of drugs can be used. Specifically, for example, prostaglandins (El, E2, F+α, F1a,
A+, I2, B+ SD2, etc.), steroidal anti-inflammatory drugs (dexamethasone, hydrocortisone, prednisolone, betamethacin, triamcinolone, methylprednisolone, etc.), non-steroidal anti-inflammatory drugs (indomethacin, acemethacin, flurbiprofen, aspirin, Ibuprofen, flufenamic acid, ketoprofen, etc.), anticancer drugs (5-fluorouracil, adriamycin, spageicomycin, benzoylurea compounds, downmycin, bleomycin, etc.), vitamins (A-KSE)
1D1COQ+o, etc.), proteins (urokinase, blood coagulation factor, blood coagulation factor ), or derivatives thereof, and the like.

In addition, the glycerylphosphoryl compound itself is a known substance, and its manufacturing method is disclosed in US Pat. Nos. 4,329,302 and 4.
It is described in No. 504474, etc.

The form of the pharmaceutical composition of the present invention is not particularly limited as long as it functions as a drug carrier, but suitable examples include fat emulsions and liposomes.

The composition and preparation method of these drug carriers are known, and the composition of the present invention is prepared by further adding a required amount of glycerylphosphoryl compound (I).

Specifically, fat emulsions and liposomes will be explained.

(1) Fat emulsion Fat emulsion consists of drug, vegetable oil, phospholipid, glycerylphosphoryl compound (1) and water.

In the case of a fat emulsion, the drug is preferably fat-soluble.

Examples of vegetable oils include soybean oil, cottonseed oil, sesame oil, safflower oil, and corn oil, with soybean oil being particularly preferred.

Highly purified refined soybean oil is generally used. Further, as for phospholipids, purified phospholipids or hydrogenated phospholipids are generally used, and those derived from soybean or egg yolk are used.

Its composition is 1-50% (W/V) vegetable oil, preferably 1-20% (W/V), 1 to 100 parts vegetable oil.
~50 parts, preferably 5-30 parts of phospholipid, i.e. 0.1-10% (W/V), preferably 0.5-5%
(W/V), glycerylphosphoryl compound (I) 0.
004-0.5% (W/V), preferably 0.02-0
．． 1% (W/V) and an appropriate amount of an aqueous solvent.

Depending on the type of drug, the concentration may be increased or decreased, as long as an effective amount is contained in the packaged unit.

The fat emulsion of the present invention further comprises up to 0.3% (W/V) of a fatty acid having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms, or a physiologically acceptable salt thereof as an emulsification aid. It's okay to stay. The fatty acid or salt thereof used as the emulsification aid is known, and any conventionally known fatty acid or salt thereof may be used. Also, 0.5% (W/V) or less, preferably 0
．． Cholesterol in an amount of 1% (W/V) or less or 5%
(W/V) or less, preferably 1% (W/V) or less, of phosphatidic acid may be included as a stabilizer.

The preparation of the present invention may also contain a polymeric substance selected from albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, and hydroxyethyl starch as a stabilizer. The amount of the stabilizer added is 0.1 to 5 parts by weight, preferably 0.5 to 1 part by weight, per 1 part by weight of the drug.

For isotonicity, commonly used tonicity agents such as glycerin, glucose, sugar alcohols, salts (eg, sodium chloride, etc.) can be added.

The fat emulsion of the invention can be prepared using a conventional homogenizer, e.g.
It is manufactured by using a pressurized injection type homogenizer or an ultrasonic homogenizer. That is, first, the required amounts of vegetable oil, phospholipid, drug, glycerylphosphoryl compound (I), and other additives mentioned above are mixed and heated to form a solution, and then homogenized with a homogenizer to form a water-in-oil solution. It can be easily produced by preparing a type dispersion, then adding the required amount of water to it, homogenizing it again with a homogenizer, and converting the dispersion into an oil-in-water emulsion. Stabilizers may be added to the resulting emulsion.

The average particle diameter of the fat emulsion in the present invention is 1.0μ or less (
It is preferable that the particle size distribution is 0.1 to 1.0μ).

The fat emulsion obtained above may be used as it is as a liquid preparation, or may be prepared as lyophilized.

Freeze-drying is carried out by means known per se. Freeze-dried preparations are generally diluted or dispersed with an aqueous solution for physiological use.

(2) Liposomes Liposomes, which are one aspect of the present invention, include drugs, phospholipids,
Consists of glycerylphosphoryl compound (I) and water.

Its composition is phospholipid 0.1-10% (W/V)
, preferably 0.5-5% (W/V), glycerylphosphoryl compound (I) 0.004-0.5% (W/V)
, preferably 0. 02-0°1% (W/V) and an appropriate amount of water.

The amount of drug added can be changed as appropriate depending on the type of drug, but -
It is sufficient that the effective amount is contained in the packaging unit.

Any phospholipid that is physiologically acceptable and metabolizable and non-toxic can be used in the present invention.

For example, phosphatidylcholine, phosphatidylserine, phosphatidic acid, phosphatidylglycerin, phosphatidylethanolamine, phosphatidylinosytonopesphingomyelin, and mixtures thereof (eg, soybean phospholipids, egg yolk phospholipids), etc. are used.

Phospholipids and glycerylphosphoryl compounds can be used in combination with solvents,
For example, it is dissolved in chloroform, ethanol, etc., thoroughly mixed, the container is dried under reduced pressure to remove the solvent, and the phospholipid is thinly attached to the inner surface of the container to form a phospholipid film. In this case, antioxidants are preferably used for the stabilization of the phospholipids, such as tocopherols (vitamin E
), preferably in a weight percent of about 0.01 to phospholipid.
Add so that the concentration is about 0.5% ("vV/W)".

It is produced by adding a drug-containing solution to this film, shaking it vigorously, and preferably applying ultrasound treatment to homogeneously disperse the lipids, thereby incorporating the drug into the voids of the resulting liposomes. Here, the solvent used in the solution may be any solvent that has denatured or degraded liposomes and is physiologically acceptable.
For example, water (preferably a phosphate buffer solution with a pH of 6 to 8),
saline, etc.), ethanol, etc.

Another embodiment of the preparation of the present invention is to add a drug to a lipid solution from the beginning, distill off the solvent to form a lipid film to which the drug is attached, and then add a solvent for the drug. Examples include a method of preparing liposome preparations by subjecting them to centrifugation treatment and the like.

In addition, when preparing a lipid film, cholesterol, phosphatidic acid, diacetyl phosphate, etc. may be added as a stabilizer.

The preparation of the present invention may also contain a polymeric substance selected from albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, and hydroxyethyl starch as a stabilizer.

The polymer substance stabilizer may be incorporated into the voids within the liposome along with the drug, or may be added to and blended into the liposome preparation incorporating the drug (ie, added/blended outside the liposome). Of course, it goes without saying that they may be blended both inside and outside the liposome.

The amount of the stabilizer added is 0.5 to 1 part by weight of lipid.
The amount is 10 parts by weight, preferably 1 to 5 parts by weight.

The method described above can provide drug-containing particles having a diameter in the range of about 0.1 to 1.0 microns, optionally with an ion exchanger for molecular sieving and removal of contaminants or educts. Inorganic adsorbent treatment can also be carried out. Liposomes loaded with drugs can be recovered as a precipitate.

For example, a medium containing liposomes can be subjected to ultracentrifugation, and the liposomes can be recovered as a precipitate.

This product is then washed with a physiologically acceptable aqueous solution if necessary, sterilized and filtered, and dispensed to prepare a pellet or suspension preparation. Formulation follows a widely known method for manufacturing pharmaceuticals. Wood preparations can also be provided as freeze-dried preparations by freezing a liquid preparation and then drying it under reduced pressure.

The main rule is that it is mainly used as an oral drug, and the dosage varies depending on the symptoms, target, etc. When used, it is generally dissolved or diluted with a physiologically acceptable aqueous solution, but it can also be tabletted, encapsulated, enteric-coated encapsulated, suspended, or placed in the neck by conventional pharmaceutical methods. It may also be granulated or powdered. (e) Effect The composition of the present invention contains glycerylphosphoryl compound (I)
By adding , it has superior accumulation, properties, and retention properties compared to conventional drug carriers.

Therefore, the accumulation and retention of drugs (anti-inflammatory drugs, anticancer drugs, etc.) at the site of onset becomes more effective, and sufficient drug effects can be expressed even at low-toxic doses.

Example 1 Fat emulsion (steroid preparation) 2 g of dexamethacin palmitate is added to 100 g of soybean oil and dissolved. To this, 12 g of egg yolk phospholipid and PAF are added.
Add 0.5 g (mixture of 1-0-hexadecyl-2-acetyl-5n-glyceryl-3-phosphorylcholine and 1-○-octadecyl-2-acetyl-5n-glyceryl-3-phosphorylcholine) and mix with a homomixer. Then 8.50ml of water and 25ml of glycerin
g and continued stirring to obtain a homogeneous suspension. This suspension was further processed using a Manton-Gaulin type homogenizer at a total pressure of 120 kg/crd1 at the first stage of 500 kg/
Emulsify by passing 10 times under pressure of c++f. This resulted in a homogenized, extremely fine steroid-containing fat emulsion. The average grain size of this emulsion is 0.2 to 0.
．． 4μ, and contained no particles larger than 1μ.

Example 2 Liposome (Adriamycin) 12 g of egg yolk phospholipid and 0.5 g of PAF (same as Example 1) were added to N
2 Dissolve in 100 ml of chloroform in a stream of gas. Place in a glass container (1β eggplant flask) and completely remove chloroform by distillation under reduced pressure.

This causes the lipids to form a lipid film on the glass wall. 10mj of purified water with 1g of adriamycin dissolved in it
2 and Vorte while keeping the temperature above 45℃.
When vibration is applied with x m1xer, multilamellar liposomes (
MLV; multilamellar vesicl
e) A suspension is formed (particle size 0.2-0
．． (about 4 μm).

It was centrifuged at 110,000g for 10 minutes and washed twice with phosphate buffer (pH 7, 2, 0,005M). The resulting precipitate was collected, suspended in physiological saline, and filtered for sterilization.
Dispensed.

Experimental Example 1 Anti-inflammatory effect of azinivant on arthritis (experiment to confirm the accumulation of the drug from its efficacy) -〇-octadecyl-2-acetyl-5n-glyceryl-3
A fat emulsion of dexamethacin palmitate (A) to which PAF was added (a mixture of -phosphorylcholine) and (B) the same fat emulsion to which PAF was not added were compared.

Mycobacterium butylicum suspended in liquid paraffin in the right hind paw of an SD rat.
was administered to create arthritis. Starting from 11 days later, each drug was administered intravenously three times every other day, and once after administration of adjuvant.
The value for the saline group was calculated as 10 from the left foot volume on day 1 and day 18.
The foot swelling rate and swelling suppression rate (%) were determined by setting the value to 0. As a result, 0. In the 3 mg/kg (as dexamethacin, the same applies hereinafter) and 0.9 mg/kg administration groups, significant swelling suppression (-test) was observed compared to the control group B, and the E Dso of the swelling suppression was 0. 11mg
/kg, and -10,000B was 0.27 mg/kg.

Table 1 Therefore, the arthritis suppressing effect of A was calculated to be 2.5 times that of B.

Experimental Example 2 Anti-inflammatory effect on carrageenan granuloma w l
Forming an air pouch under the dorsal skin of S.T.A.R. rats,
After 24 hours, a 2% lambda carrageenan solution was injected into the same site to create air pouch-shaped carrageenan granulomas.

In this model, granulation and new blood vessels are formed, and the drug is intravenously administered once a day for a total of 3 days starting from 5 days after the administration of carrageenan, which is considered to be in the proliferative chronic inflammatory phase. The tumor weight was measured. The inhibition rate (%) of each group was determined by setting the value of the saline group as 100. The results are shown in the table below, and significant granuloma suppression (-test) was observed in group A compared to group B.

Table 3 Effect ratio of A and B on carrageenan granuloma and EDso of granuloma suppression is 0.03 mg/k in group A
g, and group B was shown to be 0.072 mg/kg.

Therefore, the granuloma suppressing effect of A is calculated to be 2.4 times that of B.
The strength of the efficacy of group A was demonstrated.

As systemic effects of steroid administration, suppression of body weight gain, decrease in trunk line, and adrenal gland weight were seen depending on the dose, but when compared with Group B at the same dose, there was no significant difference between the two. Not observed (1-test).

Representative Patent Attorney (8107) Kiyotaka Sasaki (and 3 others)

Claims (4)

[Claims] (1) Drugs, phospholipids, general formulas ▲ Numerical formulas, chemical formulas, tables, etc. 3 alkyl group, R_3 is N^■ (CH_3)
_3, N(CH_3)_2, NHCH_3 or NH_
2) and water. (2) The drug is a prostaglandin, a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, an anticancer agent, a vitamin, a protein, or a radioactive isotope.
) The pharmaceutical composition described in item 2. (3) The pharmaceutical composition according to claim (1), wherein the pharmaceutical composition is in the form of a fat emulsion consisting of a drug, a vegetable oil, a phospholipid, a glycerylphosphoryl compound, and water. (4) The pharmaceutical composition according to claim (1), wherein the pharmaceutical composition is in the form of a liposome comprising a drug, a phospholipid, a glycerylphosphoryl compound, and water.