JPH10330287A - Digestive absorption promoter comprising polyvalent unsaturated fatty acid, and preparation containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a safe material having digestive absorption promotive activities for promoting the absorption in the digestive canal. SOLUTION: This digestive absorption promoter comprises a polyvalent unsaturated fatty acid. The medicine contains the digestive absorption promoter in an oil phase as an emulsion or in one homogeneous phase as a microemulsion. The polybasic unsaturated fatty acid is specifically eicosapentaenoic acid(EPA) and/or docosahexaenoic acid(DHA). The emulsion dosage form is preferably W/O/W type complex emulsion dosage form, concretely an emulsion dosage form of a water-soluble medicine having low absorptivity from the digestive tract is exemplified. The water-soluble medicine having low absorptivity from the digestive tract is a medicine impossible to be formed into a preparation as an oral preparation when intending to use the water-soluble medicine as a medicine because the water-soluble medicine has bad absorptivity from the digestive tract in spite of having water-solubility, and exemplified by insulin, vancomycin which is a peptide-based antibiotic, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a gastrointestinal absorption enhancer comprising a polyunsaturated fatty acid and a drug containing the same in the oil phase of an emulsion dosage form.

[0002]

2. Description of the Related Art Orally administered insulin passes through the same portal vein as secretion from the pancreas, so that excess insulin can be metabolized in the liver to avoid hyperinsulinemia, and it is easy to apply in daily life. It is considered to be the optimal administration method because it has certain advantages. However, since insulin has poor membrane permeability and stability in the digestive tract, there are many problems to be solved when administered orally. As an oral dosage form that avoids these obstacles and enhances absorption in the gastrointestinal tract, we have used special carriers, combined use of proteolytic enzyme inhibitors and absorption enhancers, and chemically modified insulin molecular structure. Although many attempts have been made, sufficient bioavailability has not yet been obtained.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a safe substance having a gastrointestinal absorption-promoting action for enhancing the absorption in the gastrointestinal tract. An object of the present invention is to increase the absorption in the digestive tract so that a water-soluble drug having a low absorption from the digestive tract can be orally administered.

[0004]

Means for Solving the Problems We have already made w
ater-in-oil-in-water (W / O /
It has been shown that the addition of unsaturated fatty acids having 18 carbon atoms to the oil phase of the W) complex emulsion increases the gastrointestinal absorption of insulin. Further research,
The applicability of the emulsion dosage form to water-soluble drugs having low absorption from the digestive tract, especially the W / O / W complex emulsion dosage form, and when formed into an emulsion, the oil phase contains polyunsaturated fatty acids, In particular, it has been found that the addition of DHA significantly promotes gastrointestinal absorption, thereby completing the present invention.

The gist of the present invention is a gastrointestinal absorption enhancer comprising a polyunsaturated fatty acid. The polyunsaturated fatty acid is a polyunsaturated fatty acid that is contained in the oil phase as an emulsion or contained as a uniform phase by the microemulsion. The gist of the present invention is to provide a gastrointestinal absorption enhancer comprising polyunsaturated fatty acids contained therein or contained as a uniform phase in a microemulsion. The polyunsaturated fatty acid is eicosapentaenoic acid and / or docosahexaenoic acid. Therefore, the present invention provides a gastrointestinal absorption enhancer comprising eicosapentaenoic acid and / or docosahexaenoic acid. Also, the present invention relates to eicosapentaenoic acid and / or microemulsion, which are contained in the oil phase as an emulsion or as a uniform phase.
Alternatively, the gist of the present invention is a gastrointestinal absorption enhancer comprising docosahexaenoic acid.

The present invention also provides a drug characterized in that polyunsaturated fatty acid is contained as a gastrointestinal absorption enhancer in an oil phase of an emulsion dosage form or as a uniform phase by a microemulsion. It is a gist. The emulsion dosage form is a W / O / W composite emulsion dosage form, and therefore, the present invention provides a method for preparing a W / O / W composite emulsion dosage form in which polyunsaturated fatty acid is used as a gastrointestinal absorption enhancer. The gist is a drug characterized by being contained in the phase. The polyunsaturated fatty acid is eicosapentaenoic acid and / or docosahexaenoic acid. Therefore, the present invention relates to the use of eicosapentaenoic acid and / or docosahexaenoic acid as a gastrointestinal absorption enhancer in an oil phase of an emulsion dosage form, or The gist of the present invention is a drug characterized by being contained as a uniform phase by a microemulsion. Further, the gist of the present invention is a drug characterized in that eicosapentaenoic acid and / or docosahexaenoic acid are contained as a gastrointestinal absorption enhancer in the oil phase of a W / O / W type complex emulsion dosage form. . The above emulsion dosage form is an emulsion dosage form of a water-soluble drug having low absorption from the digestive tract. The gist is a drug characterized by being contained in the oil phase of a low water-soluble drug emulsion dosage form. Further, according to the present invention, the polyunsaturated fatty acid is contained as a gastrointestinal absorption enhancer in the oil phase of a W / O / W complex emulsion dosage form of a water-soluble drug having low absorption from the gastrointestinal tract. The gist is a drug characterized by the following.
The present invention provides a drug characterized in that eicosapentaenoic acid and / or docosahexaenoic acid are contained as a gastrointestinal absorption promoter in an oil phase of an emulsion dosage form of a water-soluble drug having low absorption from the gastrointestinal tract. It is a gist. Further, the present invention provides that the eicosapentaenoic acid and / or docosahexaenoic acid are contained in the oil phase of the W / O / W complex emulsion dosage form of a water-soluble drug having low absorption from the digestive tract as a gastrointestinal absorption enhancer. The gist is a drug characterized by the fact that A water-soluble drug with low absorption from the gastrointestinal tract is a drug that cannot be formulated as an oral agent when it is used as a drug because it is poorly absorbed from the gastrointestinal tract despite being water-soluble Which are, for example, hormonal drugs, antibiotics, peptide derivatives, etc.
Specific examples include insulin, calcitonin, griseofulvin, cyclosporine, vasopressin, vancomycin and the like.

[0007]

Next, the present invention will be described in more detail with reference to preferred embodiments. In the present invention, the effect of promoting the absorption of unsaturated fatty acids having 18 carbon atoms is examined in detail using the colon and rectum as administration sites, and eicosapentaenoic acid (EPA), which is a polyunsaturated fatty acid that is often contained in fish and the like. ) And docosahexaenoic acid (DHA)
The synergistic effect of the combined use of was studied.

In the present invention, the applicability of an emulsion dosage form to a water-soluble drug having a low absorption from the gastrointestinal tract and the effect of promoting the absorption of unsaturated fatty acids, particularly DHA, are almost completely reduced from the gastrointestinal tract as model drugs. An experiment was performed using vancomycin, a peptide antibiotic that was not absorbed, that is, the effect of vancomycin on intestinal absorption promotion by a W / O / W complex emulsion containing DHA.
The results suggested that this dosage form could increase the absorption of poorly absorbable drugs from the intestinal tract. Then, C ₁₈ fatty acids and E are added to the W / O / W type composite emulsion.
It has been clarified that the addition of PA or DHA promotes the colon and rectal absorption of insulin.

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail with reference to embodiments. The present invention is not limited by these examples.

Example 1 << Method for Preparing W / O / W Type Complex Emulsion >> The emulsion was prepared by a two-stage emulsification method shown in FIG. 1 using a homogenizer. The composition is shown in FIG. As the fatty acid, oleic acid [C _18: 1], linoleic acid [C _18: 2], linolenic acid [C _18: 3] and DHA [C _22: 6] was used. The inner aqueous phase is an aqueous vancomycin solution containing 5% gelatin, the oily phase is 5% phospholipid (phosphatidylcholine: phosphatidylethanolamine = 7: 3), 20% Span80. Triglycerides, fatty acids, α-tocopherol, outer aqueous phase (outer aqu
eous phase) consists of purified water containing 3% Tween 80, and the weight ratio of inner aqueous phase: oil phase: outer aqueous phase = 1: 4: 1
5

<< Measurement Method of Encapsulation Rate >> A prepared W / O / W composite emulsion containing 2% and 15% oleic acid was put into a cellulose tube (spectrum / bore CE molecular weight cut off 5%).
0000) and 4 ° C. and 37 ° C. in physiological saline
Dialysed. Immediately after preparation, 1 day, 4 days, 7 days, 14 days, 2
One day and 28 days later, sampling was performed, and the concentration of vancomycin in physiological saline was measured.

<< Evaluation Method of Intestinal Absorptivity of Vancomycin >> Wis weighing 180-210 g fasted for 48 hours
male tar rats under pentobarbital anesthesia
The emulsion was administered by ligating both ends of the colon and rectum by the situ loop method. The dose of vancomycin was 5 mg / kg. From the jugular vein, before administration, 5 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, 180 minutes before administration
After 240 minutes, 360 minutes, blood was collected and the concentration of blood vancomycin was measured.

<< Method of Measuring Blood Concentration >> Measurement was carried out using a fluorescence polarization immunoassay. FIG. 3 shows the colon (Colon) or rectum (Rectu) after administration of the vancomycin emulsion (●) and vancomycin solution (（) containing 2% DHA.
m) shows the time-dependent change in the blood vancomycin concentration after administration.

<< Results and Discussion >> Under the experimental conditions at 4 ° C., the encapsulation rate of vancomycin in the oleic acid-added emulsion was about 50% on average irrespective of the amount of oleic acid added. Almost no change was observed in the encapsulation rate even afterwards. According to the results of in situ absorption experiments, C _{18 was found in} both the colon and rectum.
A remarkable absorption-promoting effect of the W / O / W complex emulsion containing unsaturated fatty acids was observed. Similarly, DHA
Also in addition W / O / W type multiple emulsion, vancomycin absorption promoting effect comparable to C ₁₈ unsaturated fatty acids were observed in both treatment site (Fig. 3). These suggest that this dosage form can increase the absorption of poorly absorbable drugs from the intestinal tract.

Example 2 1) Composition and preparation of W / O / W type complex emulsion An insulin solution containing gelatin as an internal aqueous phase and an oil phase were used.
Triglyceride, lecithin, lipophilic surfactant (Sp
an80), fatty acids, antioxidants (α-tocopherol)
), A hydrophilic surfactant (Tween 8)
Using purified water containing 0), homogenizer
It was prepared using an Iser. W / O / W Composite Emuljo
The composition of the aqueous solution is the inner aqueous phase (5% gelatin aqueous insulin solution).
Liquid), oil phase (5% phospholipid, 20% Span80, bird
Glycerides, fatty acids, α-tocopherol), and outside
It consists of an aqueous phase (purified water containing 3% Tween 80). Oil phase
Fatty acid to be added to stearic acid [C₁₈: 0],
Oleic acid [C₁₈: 1], linoleic acid [C₁₈: 2],
Norenic acid [C₁₈: 3], EPA [C ₂₀: 5] and DH
A [C_{twenty two}: 6], containing 2% in the emulsion formulation
Was added as follows.

2) In situ experiment Evaluation of the intestinal absorptivity of insulin was performed in situ low
Approximately 1 g of various emulsions were added to the colon and rectum of male Wistar rats weighing 180 to 220 g by the op method.
After administration, changes in blood glucose level and blood insulin concentration over time were examined. Further, in order to examine the mucosal irritation of the emulsion preparation, a histopathological examination of the colon and rectum mucosa 4 hours after the application of the emulsion was performed using an optical microscope. Table 1 shows the results of histopathological examination of the colon and rectum 4 hours after application of the fatty acid-added insulin emulsion. The blood glucose level was measured using a glucose oxidase method, and the blood insulin concentration was measured using an enzyme immunoassay method.

[0017]

[Table 1]

FIGS. 4 and 5 show an emulsion in which the dosage of insulin is 50 U / kg, triolein is used as a triglyceride, and unsaturated fatty acids such as stearic acid, oleic acid, linoleic acid and linolenic acid are added to the oil phase. Was administered to both the colon and rectum (in the case of an insulin emulsion,
% Fatty acid-added insulin emulsion □) and blood sugar level (insulin emulsion “black triangle”),
In the case of the insulin emulsion containing 2% fatty acid, the change over time in (ii) was shown. In both the colon (FIG. 4) and the rectum (FIG. 5), the blood insulin level was significantly increased, and a remarkable hypoglycemic effect was observed. On the other hand, such a blood glucose lowering effect was not observed in the emulsion administration group in which stearic acid, which is a saturated fatty acid, was added to the oil phase.

In the emulsion containing DHA and EPA, FIGS. 6 and 7 (in the case of an insulin emulsion {in the case of an insulin emulsion containing 2% fatty acid})
As is more apparent, a hypoglycemic effect comparable to that of unsaturated fatty acids having 18 carbon atoms was observed, and it was revealed that these unsaturated fatty acids have a strong insulin absorption promoting action.

Further, as is apparent from FIGS. 8 and 9, the dose dependence of the blood glucose lowering effect of the emulsion supplemented with DHA was 5, 10, 25 and 50 U / kg (control ●, 5 U / kg “black triangle”, 10 U / kg). As a result of examining the range of kg “black inverted triangle”, 25 U / kg ◆ and 50 U / kg ■), it was found that the blood glucose level and the blood insulin concentration fluctuated depending on the dose. In addition, as a result of histopathological examination of the colon and rectum after application of the emulsion, almost no change in mucosal irritation due to the W / O / W complex emulsion preparation containing DHA was observed.

From the above results, the insulin-containing W / O / W complex emulsion in which the unsaturated fatty acid is added to the oil phase can be used for targeting the colon and rectum to absorb insulin safely and efficiently. It is believed that this could be a possible formulation.

As is clear from FIG. 10, C / C ₁₈ fatty acids, EPA or DHA were added to the W / O / W type composite emulsion.
It was clarified that the addition of the compound promoted the colon and rectal absorption of insulin. Its absorption promoting action is C ₁₈ saturated fatty acid <C ₁₈ unsaturated fatty acid <EPA ≦ DH
The tendency to become strong in the order of A was recognized. In addition, as apparent from FIG. 11, it was revealed that the action of DHA was lost in the glycerol ester form.

As a result of examining the pharmacokinetics of insulin after the administration of the emulsion containing unsaturated fatty acids, as shown in Table 2 (colon) and Table 3 (rectum), the area under the blood concentration-time curve between the administration sites ( AUC) and maximum blood concentration (C
_max ) did not differ, but the time to maximum blood concentration (T _max ) and the mean residence time (MRT) tended to be longer with colon administration.

[0024]

[Table 2]

[0025]

[Table 3]

As is evident from FIG. 12, the DHA-added emulsion exhibited a hypoglycemic effect depending on the dose of insulin, and a pharmacological utilization of up to about 20% was obtained. Table 1
As shown in Table 2, almost no change in intestinal mucosal irritation was observed with this preparation, and it is considered that this preparation could be a highly useful preparation.

[0027]

According to the present invention, it is possible to provide a safe substance having a gastrointestinal absorption-promoting action for enhancing gastrointestinal absorption. By increasing the absorption in the gastrointestinal tract, it became possible to orally administer a water-soluble drug having a low absorption from the gastrointestinal tract.

[Brief description of the drawings]

FIG. 1 is a drawing illustrating the preparation of a W / O / W complex emulsion by a two-stage emulsification method.

FIG. 2 shows the internal aqueous phase (5%) of a W / O / W type composite emulsion
Gelatin-containing vancomycin aqueous solution), oil phase (5% phospholipid, 20% Span80, triglyceride, fatty acid,
1 is a drawing showing a composition comprising α-tocopherol) and an external aqueous phase (purified water containing 3% Tween 80).

FIG. 3 is a drawing showing the time-dependent change in blood vancomycin concentration after administration to the colon (Colon) or rectum (Rectum) after administration of vancomycin emulsion (●) and vancomycin solution (○) containing 2% DHA. is there.

FIG. 4 shows a dose of 50 U / kg of insulin, triolein as triglyceride, stearic acid,
Blood insulin concentration after administration to the colon of an emulsion in which unsaturated fatty acids of oleic acid, linoleic acid or linolenic acid are added to the oil phase (in the case of an insulin emulsion, □ in the case of 2% fatty acid-added insulin emulsion)
FIG. 4 is a drawing showing changes over time in blood glucose levels.

FIG. 5 shows a dose of 50 U / kg of insulin, triolein as triglyceride, stearic acid,
Blood insulin concentration and blood glucose level after administration to the rectum of an emulsion in which an unsaturated fatty acid of oleic acid, linoleic acid or linolenic acid is added to the oil phase (“solid triangle” in the case of an insulin emulsion, insulin emulsion containing 2% fatty acid) FIG. 6 is a drawing showing a change over time in case (a).

FIG. 6 is a graph showing a time-dependent change in blood glucose level (“solid triangle” in the case of an insulin emulsion, Δ in the case of an insulin emulsion containing 2% fatty acid) after administration of an insulin emulsion containing 2% DHA or EPA.

FIG. 7 is a graph showing the time-dependent change in blood insulin concentration (“solid triangle” in the case of an insulin emulsion, Δ in the case of an insulin emulsion containing 2% fatty acid) after administration of an insulin emulsion containing 2% DHA or EPA.

FIG. 8 shows the control of the dose dependence of the blood glucose lowering effect in the colon by the emulsion containing DHA. ● 5 U / k
g "Black triangle", 10U / kg "Black inverted triangle", 25U
5 is a drawing showing the results of studying the range of / U / kg and 50 U / kg.

FIG. 9 shows the control of the dose dependence of the blood glucose lowering effect in the rectum by the emulsion containing DHA. ● 5 U / k
g "Black triangle", 10U / kg "Black inverted triangle", 25U
5 is a drawing showing the results of studying the range of / U / kg and 50 U / kg.

FIG. 10 is a drawing showing that the addition of C ₁₈ fatty acids, EPA or DHA to a W / O / W complex emulsion promotes the colon and rectal absorption of insulin.

FIG. 11 is a graph showing the form dependence of blood glucose value in the colon by the DHA-added emulsion (in the case of an insulin emulsion, and in the case of various forms of DHA-added insulin emulsion).

FIG. 12 is a drawing showing an optimum use amount of a DHA-added emulsion.

[Procedure amendment]

[Submission date] June 9, 1998

[Procedure amendment 1]

[Document name to be amended] Drawing

[Correction target item name] All figures

[Correction method] Change

[Correction contents]

FIG.

FIG. 2

FIG. 3

FIG. 6

FIG. 4

FIG. 7

FIG. 5

FIG. 8

FIG. 9

FIG. 10

FIG.

FIG. 11

Continued on the front page (72) Inventor Mariko Morishita 2-4-41 Ebara, Shinagawa-ku, Tokyo

Claims (9)

[Claims] 1. A gastrointestinal absorption enhancer comprising a polyunsaturated fatty acid. 2. The gastrointestinal tract absorption according to claim 1, wherein the polyunsaturated fatty acid is a polyunsaturated fatty acid contained in an oil phase as an emulsion or as a uniform phase by a microemulsion. Accelerator. 3. The gastrointestinal absorption enhancer according to claim 1, wherein the polyunsaturated fatty acid is eicosapentaenoic acid and / or docosahexaenoic acid. 4. A drug characterized in that the polyunsaturated fatty acid is contained as a gastrointestinal absorption enhancer in the oil phase of an emulsion dosage form or as a uniform phase by a microemulsion. 5. The method according to claim 4, wherein the emulsion dosage form is a W / O / W complex emulsion dosage form. 6. The drug according to claim 4, wherein the polyunsaturated fatty acid is eicosapentaenoic acid and / or docosahexaenoic acid. 7. The drug according to claim 4, 5 or 6, which is an emulsion dosage form of a water-soluble drug having low absorption from the digestive tract. 8. The drug according to claim 7, wherein the water-soluble drug having low absorption from the digestive tract is insulin. 9. The medicament according to claim 8, which is in an oral dosage form.