JP2002037745A - Technique for ameliorating bioavailability of water- soluble hardly resorptive/low resorptive drug - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new resorption promoting technique which increases the resorption of a water-soluble hardly resorptive/or low resorptive drug from digestive tracts and is used to give an effective blood level of a drug in therapy. SOLUTION: This resorption promoting technique carried out by means of using a preparation prepared by formulating an ester mixture of a 6-18C fatty acid glycerol ester with a 6-18C fatty acid macrogol ester to the water-soluble hardly resorptive/low resorptive drug.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a formulation technique for improving the bioavailability by improving the absorption of a drug having poor or low absorption from the digestive tract after oral administration.

[0002]

[Background and Problems of the Invention] Aminoglycoside antibiotics, penicillin antibiotics, cephalosporin antibiotics, cephem antibiotics, peptide antibiotics such as vancomycin, antiviral drugs such as acyclovir, and anticancer drugs such as epirubicin. In order to increase the absorption rate after oral administration of various water-soluble poorly- and low-absorbing drugs such as, there are methods such as prodrug formation. However, since prodrugs are novel compounds, they are extremely expensive to develop. Also, development of various absorption enhancers such as capric acid has been attempted, but detailed data on safety such as tissue injury must be collected. Therefore, there is a need for a technique for improving the bioavailability of a highly soluble, water-soluble, low-absorbency drug.

[0003]

2. Description of the Related Art Various absorption enhancers such as capric acid have been developed as a technique for improving the bioavailability of a water-soluble, low-absorbency drug. But,
Problems with side effects such as tissue damage remain with absorption enhancers such as capric acid.

[0004]

The water-soluble, low-absorbency drugs include aminoglycoside antibiotics, penicillin antibiotics, cephalosporin antibiotics, cephem antibiotics, and peptide antibiotics such as vancomycin. Representative drugs include antiviral drugs such as acyclovir and anticancer drugs such as epirubicin. With these drugs,
Due to the poor absorption after oral administration, large doses must be used. Also, among the drugs currently under development, there are a number of poorly water-soluble and low-absorbing drugs like these drugs, but due to the poor or low absorption rate after oral administration, it has not been commercialized. I'm buried. If the absorption of these drugs could be increased safely, many patients suffering from the disease could be treated with oral dosage forms.

[0005]

According to the present invention, the above problems can be solved as follows. In other words, the difficulty of water solubility
When a low-absorbing drug is dissolved or dispersed together with an ester mixture of a glycerol ester of C6-18 fatty acid and a macrogol ester of C6-18 fatty acid and administered to the gastrointestinal tract, the same or better than a conventional absorption enhancer is obtained. It has been found that the absorption can be enhanced to a high degree and the bioavailability after oral administration can be improved, and the present invention has been completed.

[0006]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that glycerol esters of C6-18 fatty acids and C6- It has been invented that the bioavailability can be significantly improved by adding an ester mixture of 18 fatty acids with macrogol esters. That is,
The present invention relates to (1) a water-soluble drug having low or low absorption, and C6-
A gastrointestinal absorption preparation comprising an ester mixture of a glycerol ester of 18 fatty acids and a macrogol ester of C6-18 fatty acid; and (2) the gastrointestinal absorption of (1), wherein the C6-18 fatty acid is a saturated fatty acid. It is a highly soluble, low-absorbency drug formulation.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The water-soluble poorly or low-absorbing drug referred to in the present invention is a drug or compound which has high polarity and is very well soluble in water, and has low gastrointestinal membrane permeability even after oral administration. Therefore, it refers to drugs and compounds in general that require improved bioavailability through formulation technology.
The glycerol ester of C6-18 fatty acid is C6-18
If it contains at least one of mono-, di- and triglycerol esters of fatty acids, it is usually used in the form of a mixture thereof. The C6-18 fatty acid may be a saturated or unsaturated fatty acid having 6 to 18 carbon atoms, and is preferably a saturated fatty acid, particularly a saturated fatty acid having 6 to 12 carbon atoms, that is, caproic acid, caprylic acid, capric acid and lauric acid. .

The macrogol in the macrogol ester of a C6-18 fatty acid usually has a molecular weight of 100 to 8
And preferably 200 to 600 polyethylene glycol, and the ester thereof may be a mono- or di-ester or a mono-di-mixed ester. The C6-18 fatty acids constituting the macrogol ester are the same as those in the glycerol ester described above. The weight mixture ratio of the mixture of glycerol ester and macrogol ester is such that the ratio of glycerol ester to macrogol ester is usually 1: 0.1 to 10, preferably 1: 0.2 to 5. This mixed ester of glycerol ester and macrogol ester is a self-emulsifying base (S
elf-emulsifying agent). In the European Pharmacopoeia, caprylocaproyl macrogol glyceride
ides and described as Gattefosse s.
a.) can be conveniently used as Labrasol (trade name). In the present invention, the compounding ratio of the water-soluble low-absorbency drug to the ester is 1: 500, preferably 1: 100.

The following examples, which are not intended to limit the present invention, are further illustrated by the following examples.

[0010]

Example 1 After dissolving 5 mg of gentamicin sulfate in 1 ml of distilled water, 1 ml of labrazole was added and mixed to obtain a clear solution.

[0011]

Example 2 After dissolving 5 mg of tobramycin in 1 ml of distilled water, 1 ml of labrasol was added and mixed to obtain a clear solution.

[0012]

Example 3 After dissolving 10 mg of cefazolin sodium in 1 ml of a 10% solution of a nonionic surfactant HCO-60 (manufactured by Nikko Chemicals), 1 ml of labrazole was added and mixed to obtain a clear solution.

[0013]

[Test Example 1] Wistar male rats were subjected to laparotomy under pentobarbital anesthesia, and blank blood was collected.
2 ml of the formulation prepared in Example 1 is injected into the ascending colon. As a control, gentamicin sulfate 5 mg in distilled water 2
The aqueous solution dissolved in ml is similarly administered to another rat. Then, blood was collected from the jugular vein 30 minutes, 1, 2, 3, 4, 5, 6 hours later, and the gentamicin concentration in the plasma was measured by high performance liquid chromatography HPLC. The concentration of gentamicin in plasma was determined from the total area of components 1, 2 and 3 of gentamicin on the HPLC chart. As a result of the measurement, after administration of the gentamicin aqueous solution, the concentration of plasma gentamicin was low below the detection limit at all blood collection points. On the other hand, the gentamicin concentration in the plasma after administration of the preparation of Example 1 was 3.30 minutes later.
The value was as high as 3 (μg / ml). Thereafter, similarly, 1 hour later, 4.5 (μg / ml), 2 hours later, 4.1 (μg / ml), 3 hours later, 3.8 (μg / ml), 4 hours later, 3 (μg / ml) 0.6 (μg / ml), 5
The value was as high as 3.1 (μg / ml) after 3.0 hours and 3.0 (μg / ml) after 6 hours. In addition, gentamicin aqueous solution, Example 1
In all the rats to which the above-mentioned preparation was administered, the values before administration of gentamicin were all below the detection limit.

[0014]

EFFECTS OF THE INVENTION C6 against water-soluble and low-absorbency drugs
Method for greatly improving the bioavailability after oral administration of a water-soluble, low-absorbency drug by using an ester mixture of glycerol ester of -18 fatty acid and macrogol ester of C6-18 fatty acid as absorption enhancer Established.

Drugs that can promote absorption include aminoglycoside antibiotics, penicillin antibiotics, cephalosporin antibiotics, cephem antibiotics, peptide antibiotics such as vancomycin, antiviral drugs such as acyclovir, and epirubicin. And various water-soluble hardly- or low-absorbing drugs such as anticancer drugs.

[0016]

[Principal use] Although it is a compound with extremely potent activity in in vitro pharmacological experiments, it has only low efficacy from intestinal tract due to low absorption rate in the intestine after oral administration in vivo and existing and new compounds Formulations with improved bioavailability of compounds and drugs can be developed.

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Claims (4)

[Claims] 1. A method for preparing a water-soluble drug having low or low absorption, which comprises C6-
By adding an ester mixture of a glycerol ester of 18 fatty acids and a macrogol ester of C6-18 fatty acids, the absorption of a water-soluble, low-absorbency drug from the digestive tract after oral administration is enhanced, and the drug is circulated into the circulating blood. A formulation that can significantly increase the transfer amount of a water-soluble, low-absorbency drug, thereby enhancing bioavailability. 2. The preparation according to claim 1, wherein the C6-18 fatty acid is a saturated fatty acid. 3. The preparation according to claim 1, wherein the glycerol ester of C6-18 fatty acid is, for example, Labrasol. 4. Representative examples of water-soluble and low-absorbency drugs include aminoglycoside antibiotics, penicillin antibiotics, cephalosporin antibiotics, cephem antibiotics, and peptide antibiotics such as vancomycin. There are substances, antiviral drugs such as acyclovir, and anticancer drugs such as epirubicin. The drugs to which the present invention can be applied are not limited to these existing drugs, but also include other water-soluble and low-absorbency drugs or the drugs and drug candidate compounds to be developed in the future.