JPS61172832A - Slightly soluble drug-containing preparation composition - Google Patents

Abstract

PURPOSE:The titled composition having improved absorption characteristics in organisms, by adding previously a slightly soluble drug to a matrix structure of hydrogenated phospholipid, and pulverizing the resultant substance. CONSTITUTION:A hydrogenated substance of a phospholipid derived from egg yolk or a plant is transparently dissolved in an organic solvent such as hexane, heptane, chloroform, etc. A slightly soluble drug (e.g., coronary vasodilator such as nifedipine, etc., antibiotic such as griseofulvin, muscle relaxant such as CROZOPAZON, etc., antispasmodic such as etomidoline, antihistamine such as diphenhydramine, etc., cardiac such as digoxin, etc.) is dissolved or dispersed in the solution, the solvent is distilled away, and evaporated to dryness, to form a coarse granular substance. It is ground to give a slightly soluble drug- containing preparation composition having good adaptability to organisms, effectively improved solubility of slightly soluble drug, good absorption in organisms, and extremely high safety.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a pharmaceutical composition containing a poorly soluble drug that has been IJ-luxed with a hydrogenated phospholipid. By incorporating the added phospholipids into the matrix structure and then pulverizing them,
It has improved absorption in the body.

[Conventional technology]

Poorly soluble drugs are difficult to absorb because they are not absorbed into the gastrointestinal fluid in vivo. In order to improve the absorption of poorly soluble drugs, we used the complex-forming properties of polymeric substances such as methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, and polyamino acids to create co-precipitated compounds with drugs9. Kusubonmu, which uses phospholipids, is attracting attention.

[Problem that the invention seeks to solve]

However, methods that utilize all polymeric substances have problems in terms of biocompatibility and absorption into the body, and there are also disadvantages in terms of formulation, such as the amount of polymeric substances used in the drug being too large. many. In addition, liposomes have a low drug trapping rate;
There are many problems such as poor stability of the ribbon boom itself. Therefore, it is desired to develop a pharmaceutical composition that is compatible with the living body, effectively improves the popular understanding of aS drugs, and has good absorption in the living body.

[Means for solving problems]

Considering these demands, the present inventors focused on the excellent biocompatibility of phospholipids, and as a result of using a mold for investigation,
Once the drug is incorporated into the liquid crystal structure of the phospholipid,
The present invention was completed based on the discovery that a desired pharmaceutical composition can be obtained by forming a matrix and then pulverizing it.

That is, the pharmaceutical composition of the present invention transparently dissolves a hydrogenated product of phospholipid derived from egg yolk or a plant in an organic solvent such as hexane, heptane, or chloroform, and the drug t-dissolution or After dispersion, the drug is dried by distilling off the medium to form a coarse granular material, which is then completely pulverized to obtain a pharmaceutical composition containing the entire drug in a hydrogenated phospholipid matrix.

In addition, a suspension solution of hydrogenated phospholipid and drug in an aqueous solvent was completely concentrated to precipitate the solid content, and hydrogenated lecithin and drug were dissolved in an organic solvent at high temperature and precipitated at low temperature. The pharmaceutical composition of the present invention can also be obtained by obtaining coarse granular material and pulverizing it.

The concentration of phospholipid in the solution may be any percentage as long as matrix formation is possible.

Phospholipids are substances widely distributed in the animal and plant world, and the hydrogenated phospholipids of the present invention use phospholipids extracted from egg yolks, soybeans, etc., or phospholipids that are superior to neutral lipids as raw materials. was hydrogenated by a conventional method. The hydrogenated phospholipid preferably has an iodine value of 0 to 60,
Use one type or a combination of two or more types.

In practicing the invention, water-soluble excipients or binders can be incorporated into the organic solvent solution. When used on water-soluble excipients or binders, these act as core materials.
The dispersibility and absorption of the drug can be improved by coating the material with a hydrogenated lecithin matrix. Water-soluble excipients or binders include lactose,
White sugar, glucose, D-mannitol, hydroxypropylcellulose, PVP, PI/A.

Gum arabic, gelatin, etc. can be used.

In practicing the present invention, the oil component may be incorporated into the organic solvent solution. Such oily components include hydrocarbons such as liquid halafine, squalane, a-olefin oligomer, liquid polyimbutylene, vaseline, and paraffin wax;
Higher fatty acid esters such as cetyl inoctoate, inglovil myristate, instearyl instearate, and wax are preferred. In addition, any oily ingredients commonly used in pharmaceuticals, cosmetics, foods, etc., such as animal and vegetable oils, higher alcohols, and higher fatty acids, can be used.

Poorly soluble drugs used in the present invention include coronary vasodilators such as nifedipine, diviridamol, frenylamine lactate, and efloxate, phenytoin, zenacemide, ethylzenacemide, ethotoin, primidone, phensuximide, nitrazepan, clonazepan, and carbamazepine. Anticonvulsants, antibiotics such as griseofulvin, skeletal muscle relaxants such as clocibacin, fenoprobamate, carinprodol, antispasmodics such as etomidrine, antihistamines such as diphenhydraban, promethacin, mequitazine, flemastine fumarate, digoxin , inotropes such as digitoxin, deslancito, procylanisin, copidecarenone, antiarrhythmic agents such as phenytoin, zimviramide, diuretics such as polythiazide, methylclothiazide, trichlormethiazide, benzthiazide, spironolactone, chlorthalidone, deservidine, reserpine, methoserpyrozine, psilocinbovin, Antihypertensive drugs such as meptamate, prostaglandin F2
Hormones such as α-danazol and mevithiostane that are hardly soluble in water, or those that are somewhat soluble but have a very slow dissolution rate are used.

Furthermore, all bases and additives commonly used in pharmaceuticals can be used in the pharmaceutical composition of the present invention.

〔Effect of the invention〕

Since the pharmaceutical composition of the present invention uses phospholipids, which are one of the biological components, it has excellent compatibility with living organisms and is extremely safe.

In addition, the pharmaceutical composition of the present invention has the ability to greatly increase the solubility of poorly soluble drugs in water, and when taken into a living body, it easily dissolves in the gastrointestinal fluid and is removed from the gastrointestinal tract. Can increase absorption. Furthermore, the pharmaceutical composition of the present invention has excellent biomembrane permeability and is highly absorbed in the living body.

Further, by fully adjusting the iodine value of the hydrogenated phospholipid, the melting point and elasticity of the cymatrix can be adjusted. Further, in the pharmaceutical composition of the present invention, drug release properties, tissue specificity, drug stability, etc. can be controlled by changing the composition of phospholipids and the blending ratio of drug and hydrogenated phospholipid. The pharmaceutical composition of the present invention can be applied to a wide range of formulations such as external preparations, oral preparations, and stimulants.

〔Example〕

Examples of the pharmaceutical composition of the present invention are shown below, but the present invention is not limited to these Examples.

Example 1 Sample number ■■■ Original added soybean lecithin (iodine value 5) 75 5
0 25 Griseofulvin 25 50
75 Chloroform 100 100 1
00 In the above formulation (numbers indicate parts by weight, the same applies hereinafter), hydrogenated soybean lecithin and griseofulvin were completely mixed, heated to 40S50°C to dissolve in chloroform, and then chloroform gold was removed by drying. Coarse particulate matter?
Obtained. Then, by pulverizing this, powder samples ① to ② containing 25%, 50%, and 75% of sigriseofulvin were obtained.

Solubility test〉 Samples O to ■ each contained an amount of griseofulvin 7.06 da (■28 da, ■14■, ■9FI19), and for comparison with these samples, griseofulvin 7.06 m9f was taken.
The solubility of each sample was measured by the absorbance of griseofulvin at 57°C. The result is the first
As shown in the figure.

FIG. 1 (d) shows that in the formulation used in this example, the initial solubility of griseofulvin in water is extremely large. Although griseofulvin itself has a certain degree of solubility (59 μM), its dissolution rate in water is extremely low when used alone. The fact that the solubility at the initial stage of dissolution is extremely large indicates that when griseofulvin is taken into a living body, it is easily dissolved in the gastrointestinal fluid, increasing absorption from the gastrointestinal tract.

<Release test from Visking zube> ■～■
For comparison, samples containing 7.06q of griseofulvin and 7.061Qt of griseofulvin were placed in a Visking tube with 31R1 of water, immersed in a test tube containing 50% of water, and incubated at 37°C.
The concentration of griseofulvin released from the king tube was measured. The results are shown in Figure 2-3. It can be seen that the formulation of this example has excellent membrane permeability.

<In vitro rat intestinal run experiment> Run Nl & Wk
Take out the sample and make it into a sack (sao)' to the length of about 10 plows.
1119 content and griseofulvin 7.0d19'
The sample was placed in a 5lLC with 1d of water, immersed in 50g of physiological saline, and kept at 57°C. The concentration of griseofulvin that had passed through the intestinal tract in the external fluid was measured. The results are shown in Figure 4.5. It can be seen that the formulations of the non-examples are very easy to permeate through the intestinal tract.

Example 2 Hydrogenated soybean lecithin (iodine value) 80 phenytoin
20 chloroform
100% hydrogenated soybean lecithin and phenytoin were mixed together, heated to 40S and 50°C to dissolve in chloroform, and then the chloroform was removed by drying to obtain a coarse granular material. This was then ground to obtain a powder containing 20% of siphaate 4F.

Solubility> A plate containing the above sample total phenytoin 10II #9 was taken, and for comparison, phenytoin 10 and phenytoin were added in 20 ml of water, and the solubility at 37°C was measured from the absorbance of total phenytoin. The results are shown in FIG. In this example using hydrogenated soybean lecithin, it can be seen that the initial solubility of phenytoin is very high.

(In vitro rat intestinal tract experiment) The test method was the same as in Example 1, and the results were shown in Figure 7 when used on a child's sample containing phenytoin t-5.When used in the formulation of this example, phenytoin It is found that it is very easily absorbed in the intestinal tract.

Example 3 Hydrogenated soybean lecithin 80 parts by weight Nifedipine 20 Hexane 100 A powder containing 20% nifedipine was obtained in the same manner as in Example 2.

Solubility of nifedipine in water using the same method as in Example 2.
Examined. The results are shown in FIG.

It can be seen that the solubility of nifedipine is extremely high in this example.

<In vitro rat intestinal tract experiment> The results of a rat intestinal tract permeation experiment conducted in the same manner as in Example 2 are shown in FIG. It can be seen that the intestinal absorption of nifedipine is extremely large.

[Brief explanation of drawings]

Figures 1, 2, 3, 4 and 5 are graphs showing the test results of the sample of Example 1, respectively, and Figures 6 and 7 are the test results of the sample of Example 2, respectively. 8 and 9 are graphs showing the test results of the sample of Example 5, respectively. Applicant's agent Kaoru Furuya Figure 2 Time (minutes) Figure 5 Time (hours) Figure 4 Time (hours) Figure 5 0 0.5 1
1.5 hours (hours) Figure 7 Q O,511,5 hours (hours) Figure 9 0 0.5 1 1.5 hours (hours) Procedures (Published by Hoshosho) April 3, 1985

Claims (1)

[Claims] 1. After dissolving or dispersing a poorly soluble drug in an organic solvent solution of hydrogenated phospholipid, it is dried to form a solid with a matrix structure, and this is crushed to obtain a poorly soluble drug in a hydrogenated phospholipid matrix. A pharmaceutical composition comprising: