JPS5946228A - Preparation of water-soluble and lymph-transitional drug containing biologically active organic compound - Google Patents

Abstract

PURPOSE:To prepare a water-soluble and lymph-transitional drug advantageous in view of absorptivity and migration in the body, by mixing a water-insoluble or hardly soluble physiologically active organic compound with more than equimolar amount of tri-O-methyl-beta-cyclodextrin. CONSTITUTION:A biologically active organic compound insoluble or hardly soluble in water (e.g. non-steroidal antiphlogistic agent, anti-malignant tumor agent, remedy for leukemia, steroid hormone, digitalis glucoside, tranquillizer, fat-soluble vitamin, coenzyme Q, etc.) is dissolved in water in the presence of more than equimolar amount of tri-O-methyl-beta-cyclodextrin to obtain the water-soluble and lymph-transitional drug of said organic compound. The drug having water- soluble and lymph-transitional properties exhibits high absorptivity by oral administration. The antitumor activity, etc. of the antitumor agent, etc. can be improved and the side effects can be reduced by the selective transition of the agent to the lymph path.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the biologically 7+'i-1'l mui of water-soluble and poorly soluble Pl. 1. This invention relates to a method for producing a drug.

Some biologically active organic compounds have limited administration and routes due to poor or insufficient solubility in water, or their absorption or in vivo dynamics are related to lymphatic threads.

Or 11′! There are many things that are tides.

For example, coenzyme Q, which is a metabolic cardiotonic agent. It is known that the absorption rate of (ubidecarenone) after oral administration is 1'j through the lymphatic route, but it is poorly soluble in water, so the rate of absorption from the gastrointestinal tract is poor, and it is selectively absorbed through the lymphatic route. There are problems with biotransfer.

Similarly, vitamins 1 and K2, which are fat-soluble vitamins, are almost insoluble in water, so their absorption rate is low when administered orally, and it is not possible to use them as is. The population cannot.

In addition, many of the anti-jut/l'l tumor drugs have severe side effects, or it is because these drugs have the property of also killing tumor cells.
That is, lv-! i device selection)jI! It is caused by a lack of sex 11. It is known that the metastasis of it IIω to other organs occurs via the linkage pathway. In addition, in order to develop the excellent IjL tumor viscosity of anti-malignant 11φ tumor drugs and minimize severe side effects, it is important to selectively transfer this type of drug to the lymphatic pathway. Become.

For example, 5-fluorouracil causes gastrointestinal disorders, leukopenia, 1'V+', r'x harm, II+ disorders,
Although it has serious side effects such as photothermia, it is expected that 5-fluorouracil will exhibit excellent anti-11 tumor activity and reduce the side effect of φY by increasing the linkage transfer properties of 5-fluorouracil.

The uninvented name, etc. is hydroxyl of β-cyclodextrin, l
As a result of investigating the phase effect of tri-methyl-β-cyclodextrin, which is a compound in which the hydrogen of i (-011) is substituted with methyl- It was discovered that β-cyclokistrin increases the water solubility of insoluble or sparingly soluble organic compounds and also increases the fat solubility, and the inventors have completed the invention.

1111 In other words, the present invention provides for a biologically active organic compound that is insoluble or soluble in water ('I or if soluble 0),
- Rapid production of water-soluble and lymph-translocating mulberry shavings of biologically active organic compounds characterized by dissolution in water using I+ -0-methyl-〇-cyclotextrin]
It depends on the j method.

The water-insoluble or sparingly soluble biologically active organic compounds used here include, for example, coenzyme Q, which is a metabolic cardiotonic agent described in Section 111, fat-soluble vitamins, and JJL Malignant 1.
These include anticancer agents, non-steroidal anti-inflammatory agents, leukemia treatment agents, steroid hormone agents, digitalis glycosides, and tranquilizers.

Historically, examples of coenzyme Q include coenzyme Q,
. (ubidecarenone), fat-soluble vitamins such as vitamin 1, K2, etc., and anti-malignant 11Φ phlegm drugs such as '5-fluorouracil, -J1 steroid anti-inflammatory 1
i'l: Agents include flurbiprofen, ketoprofen, mefenamic acid, etc. Leukemia therapeutic agents include 6-mercaptopurine, steroid hormone agents, etc.
C includes hetamethasone, dexamethacin, hydrocortidine, prednisolone, progesterone, etc., examples of digitalis glycosides include dicoxin, and examples of tranquilizers include cyacepal.

The lIt of tri0-methyl-β-cyclotextrin to be added is equal to or more than 14 molar relative to the i4N compound described above.
, preferably 1 to 30 times the molar amount.

The order of addition is not particularly limited, and any of the organic compounds, tri-0-methyl-β-cyclodextrin, may be added to the water first.

The temperature during melting is 20~60°C or appropriate, and 30~4°C.
0°OM is preferred. Also, the number 11 that is safe for dissolution is 1 to 7]
1 is suitable, and it may be dissolved by applying 71-1 to 1:.

Here, all of the compounds that are 11j4 or 711 active when continuously stirred are water-soluble or highly 6
Reda.

Finally, the degree of increase of 1 was examined using the distribution coefficient as an index.

A physically 7 an+'l organic compound is saturated and crystallized in 7rnQ water, and 1 mil of chloroform and 5xlQ-'M of tri-0-methyl-〇-cyclodextrin are added thereto. 2 If! at 30°C! The difference in the concentration of the remaining organic compounds in the static water layer is the amount transferred into the oil layer, and this concentration difference is calculated as ((f: divided by the concentration) in the aqueous layer. The distribution coefficient (
P.1. 1. l+'β) was obtained by calculation 1.1.

C, 1 j! , 4q and the partition coefficient (Pc −n
,,v), and the ratio of the distribution coefficient (P,
,, uゎ, β/j, l+u) were determined by item 1 calculation.

The results are shown in Table 2.

The second table shows that biologically active organic compounds that are soluble or soluble in water, such as the partition coefficient of 2, are tri0-methyl-β-cyclotextrin. By adding 11 layers of chloropol
The fact that the transferability of

In Europe, among the preparations manufactured by the manufacturing method of A, U'^ Ming, X-ray diffraction results showed that the production of flurbiprofen, which is a steroid-based inflammatory agent, was
Absorption spectrum, ultraviolet absorption spectrum, circle (1, dimming -
1 color/1] 1 spectrum, elution test, fluorescence spectroscopy 4ji
The result of 'it' will be explained. In each analytical test, flurbiprofen-tri0-menal-β-cyclotextrin (FP-Mc-β-CyD) 1! u r
; 1 bottle once a month, 44 times for flurbiprofen (FP), a physical compound of flurbiprofen and β-cyclotextrin, flurbiprofen- 〇-Cyslodextrin (FP-β-CyD) complex
't (Physical mixture of flurbiprofen-β-cyclodextrin was used accordingly.

While analyzing the X-ray diffraction pattern shown in Figure 1, FP-Me-
β-CVD complex, FP called ii4 and Me-β-CyD
showed a different ha”turn from the physical mixture of F.
P-Me-β-C y D +M combination FP-β. Cy
Physical mixtures of D+V coalescence and FP coalescence-CyD produced different patterns. Therefore, FP and β-CyD in the image complex;)'i < is Me-β-Cyl)
It can be seen that it is a different compound from a physical mixture with.

- Also in the infrared absorption spectrum shown in Figure '52, FP-
The absorption level 1t1' of the Me-β-CVD complex is between FP and M
Physical mixtures of e-β-CyD, FP-β-CVD complexes and FP and β. The physical mixture of CyD was different in both cases. In the red 1 absorption spectrum, carphonyl (the origin of the absorption is shifted +5)
, Hl: It is determined that the carboxyl group of FP is involved in the inclusion state of both sheets.

Figure 3 shows the absorption spectra of FP China, F
The absorption wavelength of both the P-β-CVD composite and the FP-Me-β-CVD composite was approximately 250 nm 44 nm.

Also, compared to both FP, China, and Germany, the polar (absorption + +ll wavelength) of both composite f4 is shifted to the longer wavelength 011.

Next, the circularly polarized knee chromatic spectrum shown in Figure 4 is obtained. 11
Specifically, the FP-Me-β-CVD complex had a negative Koton effect of 71< shi, and the FP/β-CVD complex had a negative Koton effect of 21 K. From these midheavens, FP
It was suggested that the inclusion state of the guest molecule was different between the -Me-β, CyD+ν tone body and the FP-β-CVD complex.

In addition, according to the fluorescence spectroscopic analysis shown in Fig. 5, ・h↑light intensity is FP-β-CyDisrf than the flurbiprofen concentration.
15% in body, '35 in FP-Me-D-CyD complex
%I: )/. and Me-β-cyo
However, it was suggested that there is a small area with FP as package 1 in the Moe water + tl'l area.

Next, when the dissolution rate is calculated as 12, as shown in Figure 6 (a), the result of calculation using the rotating disk method is that the combined rate of FP-Me/β-CyD + Cy is approximately 3 (f4 1- In the fork beaker method, approximately 1
5f111 → 1. F. Compared to the dissolution rate of P, the dissolution rate of both phases is faster, especially for FP-Me-β-cyo.
The composite is about 3 (t!i) faster.

1111 As mentioned in 5, tri-methyl-β is added to organic compounds that are insoluble or biologically active in water.
-Water-soluble by adding cyclodextrin
It is clear that the amount of fat-soluble P1 increases and the fat-soluble P1 increases. -β-Cyclodextrin clathrate is formed.To clarify +5, it is clear that tri-O-methyl-β-cyclodextrin clathrate is formed for other A1-organic compounds as well. I wonder if there is one ((1).

In history, five rabbits were given flurbiprofen-tri-methyl-l (-cyclotextrin complex (FP-Mc.β-CVD complex)) produced by the production method of the present invention. The concentration of flurbiprofen in jil+ '5u was measured intravenously after the injection. flurbiprofen ir! iJ
+ II r+1riυ. Compared to the case where the risk rate is 0.1%, 41:5 (ko + m plasma 1 + flurbiprofen concentration force <
-byt.

As mentioned above, by adding tri-methyl-β-cyclodextrin to water-insoluble or soluble biologically active compound 1), the corresponding compound can be obtained.
It is possible to change the partition coefficient of organic compounds and increase fat solubility. This means that there is a positive correlation between the increase in the partition coefficient and the absorption rate.Is it generally known that 1) The absorption rate is reduced by IX?
．． Taste and add fat 764 no 1 or +P + to the lymphatic pathway/＼ migration (1 (/,) O (ability, 1z1
0, enjoy being admired. This is because the lymphatic system plays an important role in transporting fat-soluble substances, and an increase in fat solubility leads to an increase in lymph transit.

This is important for fat-soluble +11 vitamins and anticonvulsants. Since this occurs through cancer metastasis or the lymphatic route, the 11-1 drug was selected for the lymphatic route. If it is possible to reach I selectively and kill only Kan cells without harming 411 cells, it will be possible to express reliable medicinal efficacy and reduce various side effects. This is because.

Father, increasing the water solubility of the organic compound by tri-methyl-β-cyclodex1 to phosphorus matsuka is to increase the bioavailability ( Absorption rate) increases, making it possible to formulate into aqueous preparations such as Injection 4 and I-C eye drops, and improving the dispersion of blood concentration when administered with a history of 11 doses. can.

Specifically, the non-steroidal anti-inflammatory drugs flurbiprofen, mefenam 0go, and anti-inflammatory drugs are water,
Since it is poorly soluble in water, its absorption rate from the gastrointestinal tract is poor and gastrointestinal disorders are a problem, but the present invention provides a solution to these problems.

5-Fluorouracil, an antineoplastic agent, has various severe side effects111, such as gastrointestinal disorders, leukopenia, renal disorders, hair loss, and fever. By increasing the amount, it can be expected to have excellent anti-inflammatory properties and reduce side effects.

6-Melnonoptoprine, a leukocyte therapeutic agent for inl +1, also reduces the occurrence of side effects such as +11171Q, liver, kidneys, digestive organs, fever, and hair loss due to the increase in distribution coefficient and lymphatic migration, and +4 It is expected that the treatment will have a therapeutic effect. Historically, 6-mercapturin was poorly soluble in water, but with the present invention, it has become water-soluble and has IIf ability, so 11 doses can increase the absorption rate and reduce the gastrointestinal disorders associated with it. It has now become possible to reduce the amount of alcohol used and form an aqueous formulation.

Many steroid hormones, such as dexamethacin, betamethacin, hypocortisone, prednisolone, and progesterone, are all soluble in water, so their absorption rate from the gastrointestinal tract is poor. , hydrocornazone, prednisolone, etc. have gastrointestinal disorders as side effects. The present invention can be expected to reduce these side effects.

Historically, the manufacture of aqueous preparations of these steroid hormones was [
It became a Noh play.

Digoxin, a digitalis glycoside, is resistant to water and causes gastrointestinal disorders. Furthermore, digoxin has a narrow range of safe therapeutic blood concentrations, and because it is sparingly soluble in water, blood concentrations vary when administered orally. The present invention improves these problems and makes it possible to produce highly safe and effective formulations.

Diazepam, a tranquilizer, does not dissolve in water,
When administered orally, side effects such as nausea and vomiting occur in the digestive system, and since the osmotic pressure ratio of the injectable drug is approximately 30, it is often used in cases where death is difficult or in emergency situations. However, according to the present invention, it is possible to reduce the side effects even when the injection is performed using the injection method 1-1, and the pain during injection can be alleviated.

Similarly, for vitamin 8 and K6, which are fat-soluble vitamins, the increase in the partition coefficient and the ability to make them water-soluble resulted in a -1-1 increase in the absorption rate when taking a The production of non-medicated and non-permanent preparations has become possible.

Historically, the metabolic cardiotonic agent coenzyme 0. . water (ko5!1
1, the absorption rate from the gastrointestinal tract was poor, and there was a problem with selective biotransfer to the Melin route.
As methyl-β-cyclotextrin converts it into water, the partition coefficient increases: Therefore, when administered orally, absorption of gastrointestinal forces II, etc. 4 (1) I: 't It is possible to promote the transition of ＼.

In addition, conventionally, only 1F11-IJ-forms of Sodase O1O could be produced, but according to the present invention, aqueous preparations such as 71N1) and eye drops can be produced.

1. The present invention will be briefly explained by showing examples and formulation examples.

``Dog blood'' 1 Add Tory O-Menaloo β-ncrote to 100 ml of water.
Melt 71.30g of ``i'' at 30°C.
) r L, November "1"> Gradually add flurbiprofen until the added flurbiprofen no longer dissolves (flurbiprofen approx.
g) Added seaweed, 7111ifl Jk: '<4+expanded, J'l' and dissolve. Mixture'i? Ji
In total, 61 players made 1,000 shots and 4B7 made 1JJ7 throws. IU p) I511 of flurbiprofen in Yutaka Leda
& was t1896g/100d. The M degree of flurbiprofen at 1'1 of the same article is 0.059 g/
100m (!), so it's covered in water-soluble crab (').

T horn 6L (Row 2 Ketoprofen approx. 2.5g, betamethasone approx. 1.0g,
〒 Quinamethacin approximately 1.5g, Hytrocornasone approximately 5.0g
g + nil l/nisolone approx. 3.0 g, progesterone approx. 5
．． Using a large amount of about 3.0 g of Og, dioxine, and the same method as in Example 1, the l and 7H degrees of each organic compound in iW rlv were measured. The resulting tree of each mulberry is
IQ ('IQ) It is listed in Table 3 along with the jump rate.

Table 3 *Concentration of c,,,,β-0-methyl-β-cyclodextrin iod (g/'100 mQ)**
Moisture content in the absence of Co: l-0-methyl-β-cyclodextrin (g/100 mQ) All of the compounds were 9 to 258 times more water soluble.

Example 3 7.13 g of tri-methyl-β-cyclodextrin was dissolved in 100 mQ of water at 45°C, and 6-mercaptopurine was gradually added while stirring. 1. After adding until no longer dissolved (approximately 0.2 g of 6-mercabutopurine), 7111ffl
4hq '6A R'l J'l' L/te1 understand. ? I passed v1 of il matter, 61 people of insoluble matter, and 1 of insoluble matter.
Star. The concentration of 6-mercabutopurine in the obtained C) solution was (L 147 g/100 mQ. The concentration of Merno J Pudding was 0.012g/100-.

Tenj blood f row 4 Jiaseha Buddha approx. 2.5g, mehuena lx Nh q,,I
The concentration of cyasebam was 0.199 J!/10.
0 mQ, mefenamic acid Ll, 060 g/100 servings. tri0-menalu β-cyclodextrin 4
The concentration of 1゛existence is +111 or 0-05, respectively.
5g/100mQ, the latter 0.014g/100m
There was a Q.

Ten J blood 1 row 5 Dissolve 713 g of tri-methyl-β-cyclodextrin in 100 mQ of water at 40°C, and gradually add 5-fluorouracil while stirring. −・until it no longer dissolves (5−
After adding about 15 g of full louracil, 5) dissolve in a funnel. Pass the mixture, add 211 cows/solutes, and θ11 each? tl. 1. J r, 7) got 5-
The concentration of fluorouracil was 13.92 g/100 d.

Tri-O-methyl-β-cyclotextrin
It was 2.90g/100mQ.

') Dissolve 0.713 g of tri-menal-β-cyclodextrin in 100 mQ of Al6 water at 30°C, stir, and gradually add coenzyme Q. Added coenzyme Q1o
or longer until it no longer dissolves (coenzyme Q about 0.0
2g) After adding 71! Stir +111 and finish melting. ￥ Pass the IL compound for 1 time to remove insoluble matter (,,
The concentration of coenzyme Q10 was 0.015 g/100 mQ.
Coenzyme Q,. The concentration of is 0.0009g/100m
It was Q.

Mitsuno 11-eup (!IJ7 Vitamin 1 approx. 0.02g, vitamin 2 approx. 0.05g
Solving IQ'l using the same method as in Example 6 using
We measured the moisture content of each organic compound in L.

The 61 degrees are 1 to 0 in vitamins. Or43g/1(1
0ml, vitamin, 0.031'l1g/100
It was mu. l-IJ-0-methyl-β-cy))
Lotextrin - 11 right 71 de The concentration under the same conditions is Tomo 1
)1! The latter is 0.0031g/100d, the latter is 0.0
044g/100mQ.

Formulation Example 1 Flurhybrothientri 0- prepared in Example 1
Menalu β-cyclodextrin solution 11 (7100 d) was lysed and dried to obtain a powder. To this powder was carefully added 1 ml of stearin and magnesium and mixed uniformly to obtain drug 119.

Formulation Example 2 Example 3+'-J+Leaked 6-mercabutoprine tri0-methyl-β-cyclotextrin'IN ft
'2100+l+/! Lyophilize to obtain 7. powder. This powder was made into a trapezoid for 111 days using the usual 0)l:Iλ method and sieved to obtain fine granules for 11 days.

Manufactured f11J J row 3 top and bottom 1 + 115? 4 p) Dry the 5-fluorouracil-tri-0-methyl-β-cyclodextrin bath solution and remove the powder. Add starch and milk to this powder! , crystalline cellulose and methylcellulose were respectively added in appropriate amounts, mixed uniformly, granulated, rolled in 1 mm, and sieved to obtain granules.

Formulation Example 4 Coenzyme Q, -1-
Lee〇-menaloo β-citalodextrin 'tfl'
Run filter with RO100mu (pore size 0.
22 μm) Draw with one trowel, and add 4+J of injections and eye drops by adding equal lengths of sodium chloride or the like.

[Brief explanation of the drawing]

Figure 1 (a) [mouth] CJN (b) shows the X-ray diffraction pattern; Figure 1 (a) shows the FP-β-CyD physical mixture; Figure 1 (b) shows the FP-β-CyD complex,
Figure 1 C1 is a physical mixture of FP-Me-β-CyD;
Figure 1) shows the FP-
After the Me-β-CyD complex/] Lisu diagram, Figure 2 (
A) (B) is a scrap diagram of the infrared absorption spectrum, and Figure 2 C.0 is for the FP-β-cyo system, and Figure 2 (B) is for the FP.
-Me-β-CyD thread, Figure 3 is FP-Meβ
- The purple color of the CyD complex [absorption scale 1 to /1] Figure 4 is a diagram showing the circularly polarized light I-chromatic scale /7 of the FP-1-β-CyD complex, Figure 5 The diagram shows FP-crotch-β-Cy
A diagram showing the results of fluorescence spectroscopic analysis of the D complex, Figure 6 [A]
[Opening] is a diagram showing the dissolution rate of FP from the FP-Me-β-CYD complex; Figure 6 (a) is the dissolution rate by the rotating disk method, and Figure 6 (b) is the dissolution rate by the beaker method. Figure 7 shows the phase 1 of the FP-Me-β-cyo complex.
The relationship between 111j and plasma f1 degree after 1-1 injection U is
This is a diagram. Patent issue 1≦IO agent et al.”
-IEa='r悄 1st figure 2θ(0) 2nd figure (mouth' FP-Me-/?-6,.o(cm-11

Claims (1)

[Claims] l) 41 biologically active compounds that are insoluble or poorly soluble in water are dissolved in water using tri-methyl-β-cyclodextrin in an amount of at least 100%. 1. A method for producing a biologically active organic compound that is water-soluble and lymph-transferable. 2) The production method according to claim 1), in which Jl, a steroid (III)-based anti-inflammatory agent is used as the biologically active organic compound. 3) The manufacturing method according to claim 1), which uses an anti-malignant I) Φ tumor agent as the biologically active organic compound. 4] The manufacturing method according to claim 1), in which a leukemia mitigating agent is used as the biologically active organic compound. 5) The manufacturing method according to claim 1), which uses a steroid hormone as the biologically active organic compound. 6) The method for producing claim 4, wherein digitalis glycoside is used as the biologically active organic compound. 7] The method for producing Ju according to claim 1), in which a tranquilizer is used as the biologically active organic compound. 8) The production method according to claim 1), which uses fat-soluble hitamine as the biologically active compound. 9) Claim 1i which uses coenzyme as a biologically active organic compound? The manufacturing method described in Item 1 of Box i. 10) In water; soluble or sparingly soluble biologically active 41
Inclusion compound 4, which is formed by including a functional compound with tri-0-methyl-β-cyclodextrin. 11] Biologically active organic compounds include non-steroidal anti-inflammatory agents, anti-malignant tumor agents, leukemia 7-hour therapy, steroid hormones, digitalis glycosides, psychoactive substances, fat-soluble vitamins, and coenzymes. . The compound described in Section 10) of Patent No. 5-j, which is any one of the following.