JPS632414B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides cytidine diphosphocholine (hereinafter referred to as
The present invention relates to a pharmaceutical composition suitable for oral administration containing CDP-choline). More specifically, the present invention relates to a pharmaceutical composition containing CDP-choline bound to a phospholipid substance and suitable for oral administration. It is known that CDP-choline is used in the treatment of several pathological conditions in humans.
A typical therapeutic feature of CDP-choline is the treatment of impaired consciousness due to cranial damage or endogenous diseases, such as hemorrhage due to atherosclerosis, cerebral thrombosis, and brain damage. It has also been shown to be useful in treating Parkinson's disease-like syndromes. In explaining the therapeutic action of CDP-choline, it must be taken into account that CDP-choline is a precursor in the biosynthesis of phospholipids. In this regard, CDP−
The biochemical significance of choline is well established, and 100-1000 mg per day is administered to humans. The usual dosage form is parenteral, and generally contains 5-25% CDP-choline as the active ingredient.
(W/V) is administered in an aqueous solution. Pharmaceutical compositions containing CDP-choline that are actually used are not suitable for oral administration in any case. This is because CDP-choline is poorly absorbed and is also susceptible to degradation in the gastrointestinal tract by enzymes present there. CDP
- The lack of orally administered preparations containing choline has not been acknowledged to date, greatly limiting the therapeutic use of CDP-choline itself. An object of the present invention is to provide a pharmaceutical composition containing CDP-choline or a salt thereof as an active ingredient, which can eliminate the above-mentioned conventional drawbacks. That is, the present invention relates to a pharmaceutical composition suitable for oral administration containing CDP-choline or a salt thereof bound to a substance containing phospholipids. As used herein, a bond refers to a physicochemical association or a molecular combination. Examples of phospholipids include lecithins. Physical association is suitably obtained by adding and mixing phospholipids in solid state, emulsion state or solution state to an aqueous solution of CDP-choline or its salt. Protein-like substances and cross-linking agents are used to improve the stability of the association.
agent) may be appropriately blended. Preferred protein-like substances are, for example, serum albumin, egg albumin or other edible albumins. Further, as the crosslinking agent, for example, formalin or the like is preferable. The weight ratio of CDP-choline/phospholipids is 1:
The range of 20 to 1:0.5 is preferable. The pharmaceutical composition of the present invention is a novel pharmaceutical composition that is much more useful than the usual CDP-choline aqueous solution that has been conventionally used for treatment. Apart from being able to administer CDP-choline orally,
A remarkable synergistic effect on the therapeutic activity of CDP-choline was observed. This was demonstrated using a pharmaceutical composition containing ¹⁴ C-labeled CDP-choline. EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to these Examples. Example 1 (Production of CDP-choline associated with phospholipid) 100g of sodium salt of CDP-choline was added to 100ml of water.
It was dissolved in Separately, 400 g of granular vegetable phospholipid was prepared in a container equipped with a stirring device. While stirring the phospholipid granules at a constant speed,
Aqueous solution of sodium salt of CDP-choline is atomized,
The granules are then placed under vacuum or non-vacuum.
Dry in an oven at 70-80°C. The CDP-choline content thus obtained was the same in all samples taken from different parts after extraction. The prepared product had CDP-choline associated with phospholipid, was physicochemically uniform, and was suitable for preparing a pharmaceutical composition suitable for oral administration. Following the same procedure as above except that the ratio of CDP-choline/phospholipid was changed, preparations were obtained in which the weight ratio of the two compounds was 1:20 to 1:0.5. As mentioned above, the physicochemical stability of the formulations according to the invention can be improved by proteinaceous substances and crosslinking agents. Example 2 An aqueous solution obtained by dissolving 100 g of CDP-choline in 100 ml of water containing 5 g of serum albumin was sprayed onto 400 g of phospholipid granules in the same manner as in Example 1. The coated granules were again sprayed with 100 ml of water containing 5% formaldehyde as a crosslinking agent while stirring. The obtained substance was finally dried in the same manner as in Example 1 to obtain the preparation used in the present invention. Test example (absorption of ¹⁴ C-labeled CDP-choline associated with phospholipids and its distribution state by oral administration) ¹⁴ C-labeled CDP-choline (hereinafter referred to as ¹⁴ C- A preparation used in the present invention was prepared in the same manner as in Example 1, except that CDP-choline (referred to as CDP-choline) was added. The labeled carbon atom is the carbon atom of the methyl group of the choline moiety. In general, the concentration of ¹⁴ C radioactive material was 50 .mu.Kyries per gram of CDP-choline. (A) Aqueous solution of ¹⁴ C−CDP−choline and ¹⁴ C−
An aqueous suspension of the CDP-choline and phospholipid formulation was administered by gastric gavage to rats having an average body weight of 200 g. The dose was equivalent to 50 mg of choline. A fixed amount of blood was collected at different time intervals, and rats were dissected 24 hours after the start of the experiment. Radioactive material concentrations were measured in predetermined volumes or weights of serum in various organs or tissues. The results of time-dependent changes in serum concentration are shown in FIG. 1, and the concentrations in organs are shown in Table 1.

[Table] In Figure 1, the ordinate is the radiation dose (unit: c.
pm×10 ^-3 ), and the abscissa is in hours (unit:
time). ○ is the result for an aqueous solution of ¹⁴ C-CDP-choline, ● is the result for ¹⁴ C-CDP
- Results for the pharmaceutical composition of the present invention consisting of choline and phospholipids. As is clear from Figure 1 and Table 1, the radioactive substance concentrations recorded from the serum and blood of organs or tissues were higher in those administered the composition of the present invention than in those administered only the aqueous solution of ¹⁴ C-CDP-choline. It shows a higher value than the one administered. From the above results, it is clear that the pharmaceutical composition of the present invention is suitable for oral administration. The therapeutic advantages of the pharmaceutical compositions of the present invention extend beyond the fact that they provide a painless method of administration, as evidenced by the high levels of radioactive material retained in the serum. Another advantage is that pharmacological effects can be maintained for a long time with only one administration. (B) The following test was conducted using two macaque monkeys (cynomolgus) weighing approximately 2 kg. ¹⁴ C− with a radioactive substance concentration of 0.1 μKyries/mg
CDP-choline at 25mg/Kg body weight (2.5μ Curies/
(equivalent to Kg body weight) administered intravenously at once. Then at the time of administration and 5 minutes, 10 minutes, 15 minutes, and 30 minutes after administration.
Blood samples were collected at 30 minutes, 60 minutes, 2 hours, 4 hours, 7 hours, 24 hours, and 30 hours, and the DPPM (dpm) concentration in each serum was measured.
From the graph of the concentration-time curve of DM in serum, the apparent desorption rate constant (β value) and biological half-life from the living body can be calculated. These values are used to calculate the area under the serum concentration-time curve (hereinafter referred to as AUC) after 30 hours, which is necessary to estimate the total DM concentration-time curve in the same monkey. . AUC up to 30 hours after administration is calculated by trapezium methods. After the end of this test, the same monkeys received two doses of the composition of the present invention.
It was administered at three different doses. as a control
CDP-choline was orally administered in an amount corresponding to the dose of the composition of the present invention (control administration). Each test was conducted 10-15 days apart. CDP
- The doses expressed in the amount of choline are 200 mg/Kg body weight and 400 mg/Kg body weight, corresponding to radioactive substance concentrations of 2 μKyries/Kg body weight and 4 μKyries/Kg body weight, respectively. The order of each test was randomized and performed in duplicate on two animals. After administration
A series of test blood samples were collected until 30 hours had elapsed, and the DM concentration in each serum was measured. AUC can be calculated within 30 hours of administration based on one DM concentration-time curve. 0-24 hours, 24 hours after each dose, including intravenous doses.
Urine was collected at each period of ~48 hours and 48-72 hours, and the percentage of CDP-choline excreted in the urine was determined. Tables 2 and 3 show the results. Table 4 also shows the average and relative standard deviation of the results obtained using two monkeys (Tables 2 and 3). In Tables 2-4, the compositions of the invention are designated as ASONIC. Figures 2 and 3 show graphs plotting the data shown in Tables 2 and 3, respectively.

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[Table] Figure 4 shows the average concentration-time curve of intravenous administration of CDP-choline and the composition of the present invention.
200mg/Kg body weight and 200mg/Kg of the composition of the invention
Figure 2 shows the average concentration-time curve of DM when administered orally. Figure 5 shows the DPEM average concentration-time curve and CDP when the composition of the present invention is orally administered.
- Shows the DM average concentration-time curve when choline is orally administered. In Figures 2 to 5, ■ is ¹⁴ C−CDP−
25mg of choline/Kg body weight (2.5μ Curies/Kg body weight)
When administered intravenously, ○ indicates when the composition of the present invention containing ¹⁴ C-CDP-choline at 200 mg/Kg body weight (2μ Curies/Kg body weight) is orally administered; ●
When the composition of the present invention containing ¹⁴ C-CDP-choline at 400 mg/Kg body weight (4μ Curies/Kg body weight) is orally administered, △ means ¹⁴ C-CDP-choline at 200 mg/Kg body weight.
mg/Kg body weight (2μ Kyuri/Kg body weight) When administered orally, ▲ means 400 mg/Kg of ¹⁴ C-CDP-choline.
The results are for oral administration of body weight (4μ cuyries/Kg body weight). As is clear from Tables 2 to 4 and Figures 2 to 5, when the composition of the present invention is orally administered, ¹⁴ C
- Shows significant absorption of CDP-choline. That is, when the composition of the present invention is administered, the time to reach the maximum concentration point is faster than that when the control administration is performed, and the maximum concentration is lower than that of the control administration ( ^14C -CDP-choline) at any of the two dosages. clearly higher than that of single administration). The difference is especially obvious when the dose is low (see Figure 5). The absolute bioavailability of the pharmaceutical compositions of the invention was demonstrated to be greater than 50% in monkeys. That is, the F value at each dose of CDP-choline was as follows. 200 mg/Kg body weight→F=0.5109 400 mg/Kg body weight→F=0.7781 On the other hand, when CDP-choline was administered alone, the absolute bioavailability at each dose was found to be considerably lower. That is, 200 mg/Kg body weight→F=0.2143 400 mg/Kg body weight→F=0.6174 Thus, the pharmaceutical composition of the present invention is absorbed over a wide range, and the rate of absorption clearly increases with the dose. From the above test results, when the pharmaceutical composition of the present invention was compared with intravenous CDP-choline,
It has excellent absolute bioavailability.
The absolute bioavailability in the present invention was more than 50% at low doses and even close to 80% at high doses. On the other hand, in tests using rats, almost the entire dose was absorbed. In the pharmaceutical composition of the present invention, the kinetic or oral bioavailability is significantly improved. This is because absorption occurs more rapidly and is mostly absorbed at low doses. Furthermore, the rate of absorption in monkeys was higher than that observed with a single dose of CDP-choline.

[Brief explanation of the drawing]

Figure 1 is a graph showing the blood radiation dose-time curve of ^14C -CDP-choline in rats, and Figures 2 to 5 are graphs showing the serum DM concentration-time curve of ^14C -CDP-choline in monkeys, respectively. It is a graph showing a curve.

Claims (1)

[Scope of Claims] 1. A pharmaceutical composition suitable for oral administration, comprising granules of phospholipids coated with an aqueous solution containing cytidine diphosphocholine or a salt thereof. 2. The pharmaceutical composition according to claim 1, comprising a protein-like substance and a crosslinking agent. 3. The pharmaceutical composition according to claim 1, wherein the weight ratio of cytidine diphosphocholine or its salt to phospholipid is 1:20 to 1:0.5.