JP2877725B2 - Orally ingestible composition producing microemulsion - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical or cosmetic composition, especially an orally ingestible composition, capable of reacting with a human body fluid to form a microemulsion in a living body. . More specifically, the present invention specializes in "SMEDDS" (self micro e
mulsifying drug delivery system). This system has the property of emulsifying with water at the same temperature as human body temperature. This composition allows one or two or more active ingredients, regardless of their solubility, to reach a tissue, form a microemulsion by a biological fluid of the human body, and dissolve in the microemulsion one or two active ingredients. It is intended to improve the bioavailability of more than one active ingredient.

[0002]

BACKGROUND OF THE INVENTION As is well known, microemulsions are homogeneous, flowable, stable solutions comprising a hydrophilic phase, a lipophilic phase, and at least one surfactant (T
A) and at least one co-surfactant (Co
TA). Microemulsions have been widely studied for oil recovery. This point will not be described in detail here.

[0003] A surfactant is a compound having two polar groups or ionic groups having high hydrophilicity and a hydrophobic group containing a long-chain aliphatic group to some extent. The purpose of the extremely hydrophilic compound is to form micelles in an aqueous solution and an organic solvent. Auxiliary surfactants, also called "auxiliary surfactants", are compounds similar to surfactants, but with high hydrophobicity and a mutual solubilizing effect between the aqueous and oil phases of the microemulsion. It is intended to cause

[0004] An object of the present invention is to increase the bioavailability of a poorly soluble active ingredient by solubilizing the active ingredient with a microemulsion.

[0005] European Patent Publication EP-A-033
At 4777, Applicants have demonstrated that microemulsions are available in the pharmaceutical industry. Also, in PCT Publication WO 93/12766, the applicant has described a specific composition utilized as a medicament, which is a microemulsion intended to be prepared as a suppository, with rectal fluid as the hydrophilic phase. there were. This method has been successful for suppositories, but is not suitable for orally ingested compositions. This is because the volume of biological fluid in the stomach or intestine is much larger (several deciliters) than in the rectum.
That's why. On the other hand, PCT Publication No. WO 93/1276
Only a small amount of water (several milliliters) is required to form a microemulsion as described in 6.

[0006] European Patent Publication EP-A-015
No. 2945 is a mixture comprising C2-C4 oleic alcohol or alcohol polar ester, a lipophilic phase formed from C8-C12 fatty acids, and ethoxyl glycerin as a surfactant, containing 35 to 85% by weight of water. The system was described. This formulation does not become a capsule because it contains a significant amount of water. In addition, since the composition containing water produces a macroemulsion instead of a microemulsion in a living body, the bioavailability is significantly reduced.

PCT published after the priority date of this application
In published publication WO 93/23083, the anhydrous hydrophilic phase is C
A system composed of 8-C10 short chain polyglycol glycerides has been described. This system does not provide a significant improvement in the membrane diffusion of the active ingredient. The bioavailability remains unchanged since the hydrophilic active ingredient cannot be reached and no emulsion can be formed, nor can microemulsions be formed in vivo.

In the pharmaceutical and cosmetic industries, capsules, tablets, and plasters are easier to package and the demand for aqueous phase-free compositions is increasing. The compositions known to date for the production of capsules, in particular the capsules described in the above-mentioned documents, are not preferred, since the water contained in these mixtures is not suitable for the capsule production technology.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems. The present invention is an orally ingestible composition, especially a composition for pharmaceutical or cosmetic use, comprising a lipophilic phase, at least one surfactant, and at least one co-surfactant, It is intended to form a microemulsion by contacting a biological fluid, to promote the dissolution of an active ingredient in a living body, and to improve its bioavailability.

[0010]

The orally ingestible composition according to the present invention is a composition capable of forming a microemulsion, comprising at least an active ingredient and a mixture of glyceride and fatty acid ester. Lipophilic phase, surfactant (TA), and co-surfactant (CoT)
A) and a hydrophilic phase, wherein said lipophilic phase comprises a mixture of C8 to C18 polyglycol glycerides, wherein the hydrophilic-lipophilic balance (HLB) is less than 16,
And the lipophilic phase is 1% to 75% of the total weight of the composition and the surfactant (TA) is selected from the group consisting of C8 to C10 saturated polyglycol glycerides and polyglycerin olein esters; HLB is 1
6, wherein the co-surfactant (CoTA) is selected from the group consisting of propylene glycol lauric ester, polyglycerin oleic ester and diglycol ethyl, with a TA / CoTA ratio of 0.1.
5 to 6, characterized in that the hydrophilic phase of the final microemulsion is formed after ingestion of the digestive environment by biological fluids.

In short, the present invention relates to a method in which a particular lipophilic phase is selected and then combined with a particular surfactant and a co-surfactant to form a microemulsion from human or animal stomach and intestinal biological fluids. There is a feature in making it happen.
Therefore, there is no need to introduce an external hydrophilic phase to form a microemulsion. This composition improves the bioavailability of the active ingredient in vivo. The composition according to the invention can therefore be effectively taken orally.

Surprisingly, the use of a long-chain lipophilic phase significantly improves the membrane diffusion and passage of the active ingredient into the blood. In the present specification, “polyglycol glyceride” is a monoglyceride, a mixture of diglyceride and triglyceride, a mixture of polyethylene glycol (PEG) monoester and diester, or a mixture of glycerin and free PEG having a molecular weight of 200 to 600. The HLB value is adjusted by the chain length of the PEG, the melting point is the chain length of fatty acid, PEG and the degree of saturation of the fatty chain,
That is, it refers to a mixture adjusted by the chain length of the initial oil.

Further, "from C8 to C18 (C8-C18)
Fatty acids "include caprylic acid (C8), capric acid (C1
0), lauric acid (C12), myristic acid (C1
4), palmitic acid (C16), stearic acid (C1
8) is a mixture obtained by combining each of them in various ratios equal to or greater than a certain value, regardless of whether these acids are in a saturated state or not.
Refers to a mixture of C8-C18. The ratio of these fatty acids depends on the initial oil.

Since the polyglycol glyceride of the lipophilic phase is in a saturated state, it is possible to mix a solid at an ambient temperature with a liquid at a human body temperature. The HLB of this mixture is lower than 16, preferably between 9 and 15, preferably around 14, and the applicant has stated that "GELUCIRE 44 /
14 "is the same type as that commercialized under the registered trademark. In fact, if the HLB value exceeds 16, the hydrophilicity of the mixture becomes too high, which is not preferred for microemulsions. It has been found that the best results are obtained since the microemulsion can be produced in the widest range when the HLB value is about 14.

In another embodiment of the present invention, a mixture of an unsaturated C8-C18 polyglycol glyceride having an HLB of 6 and a liquid at an ambient temperature, such as "LAB"
Mixtures commercialized under the trademark "RAFIL WL 2609 BS" can be used.

The weight ratio of the lipophilic phase may range from 1% to 7% of the composition.
Preferably 5%, preferably 10% to 75%. It has been confirmed that a microemulsion that can be sufficiently diluted is not generated in this range.

The surfactant (TA) is preferably C8-C10 if the HLB is less than 16, preferably from 5 to 14.
Made of polyglycol glyceride, the applicant of which
BRAFAC CM 10 "," LABRAFAC H
A surfactant similar to that commercialized under the registered trademark of “YDROPHILE” or “LABRASOL”.

In another embodiment of the present invention, the surfactant (TA) comprises a polyglycerin oleic ester having an HLB of 10 and is assigned by Applicant to "PLUROL OLEI".
It is the same type of surfactant commercialized under the trademark "QUE". The co-surfactant (CoTA) is diglycol ethyl (also called diethylene glycol monoethyl ether), the applicant of which is “TRANSCU”.
Auxiliary surfactants similar to those commercialized under the trademark "TOL". In another embodiment of the present invention, the co-surfactant (CoTA) consists of propylene glycol lauric ester and has a "LAUROGLYC"
It is a type of co-activator commercialized under the registered trademark "OL".

In another embodiment of the present invention, the co-surfactant (CoTA) comprises a polyglycerin olein ester and is assigned by Applicant to "PLUROL OLEIQ".
It is an auxiliary surfactant of the type commercialized under the registered trademark of "UE". The TA / CoTA ratio is between 0.5 and 6
If possible, 1 to 2 is preferable. More than 6,
Also, below 0.5, the composition cannot produce a highly dilutable microemulsion.

One of the major advantages of the present invention is that, regardless of the volume of gastric juice or intestinal fluid of humans or animals (about several deciliters), the active ingredient is easily dissolved from a mixture of the volume and the composition. An emulsion is formed, and even if a large amount of biological fluid is used, its bioavailability can be increased.

Therefore, it is necessary to determine a range in which the microemulsion is generated. In this regard,
While maintaining the ratio of surfactant TA / co-surfactant CoTA to 1, a pseudo-ternary diagram was drawn. Change the ratio,
A mixture of lipophilic phase + TA + CoTA was made. The hydrophilic phase was then added dropwise until each of the mixtures became a clear solution. The amount added is the minimum proportion of the hydrophilic phase necessary to reach the range where the microemulsion occurs. This is the so-called entrance ratio. Then the addition of the hydrophilic phase is continued until clouding occurs. The amount added corresponds to the so-called outlet ratio.

The method of drawing a pseudo three-component diagram is called "titration method". The range in which a microemulsion, ie, a clear solution, occurs is between the two ranges in which the dispersed phase produces an emulsion that takes on a milky white color.

The initial composition is intended to be consumed,
It is assumed that it does not contain moisture, but depending on the application, it may be more effective to contain moisture. The condition is that the initial moisture does not contribute to the generation of the final microemulsion.

In fact, when the composition is a liquid, ie it is inherently hygroscopic and is packaged as a capsule, a small amount of water helps to control the water in the capsule. It is clear that this moisture does not contribute to the formation of the final microemulsion but merely serves to stabilize the capsule and to avoid making the capsule brittle.

FIGS. 1 and 2 are pseudo-ternary diagrams of two preferred compositions of the present invention. In each case, the mixture of surfactant (TA) and co-surfactant (CoTA) is the same. However, the lipophilic phases are different. Looking at the two figures, it can be seen that the range in which the microemulsion occurs is very wide, and corresponds to the case where the proportion of the hydrophilic phase is high (0% to 60% in FIG. 1, 0% to 70 in FIG. 2). I understand clearly. That is, microemulsions occur even in digestive organs (about several deciliters) where a large amount of biological fluid is present.

[0026]

EXAMPLES Preferred examples of orally ingestible compositions for producing microemulsions according to the present invention are described below.
The effects of the present invention will be described. However, it goes without saying that the content of the active ingredient depends on the dose of the active ingredient to be taken.

In all of these examples, 10
0% by weight of complement is an anti-inflammatory agent of indomethacin in Examples 1 to 8, 11 and 12, hydrocortisone in Example 9, and diclofenac sodium in Example 10.

Example 1 A lipophilic phase having a melting point of 48
C8-C18 polyglycol glycerides having an HLB of 9 ° C. and a GELUCIRE 4
A product commercialized under the trade name "8/09" was used.
This lipophilic phase is 73.7% of the total weight of the final composition.

The surfactant (TA) and the auxiliary surfactant (C)
oTA) is a C8-C10 polyglycol glyceride (TA) with an HLB of 10
AFAC CM 10 ”and propylene glycol / lauric ester (CoT
A), a mixture of products that the applicant has commercialized under the trade name “LAUROGLYCOL”. The weight ratio of this mixture is 18.5% of the composition and the ratio of TA / CoTA is 0.5.

The composition thus obtained is a solid whose temperature is equal to the ambient temperature and liquefies at 37 ° C. This composition has a number of advantages when compared to conventional formulations using the same active ingredient. It can be pointed out that this active ingredient, despite being lipophilic, shows good solubility in the digestive environment, ie good bioavailability.

In a dissolution test performed in a glass container in a digestive environment with a pH of 1.2, it was proved that in the case of this formulation, the ratio of the dissolved active ingredient after one hour was 48%. In order to conduct a comparative experiment, the test was conducted using a pure active ingredient (indomethacin).
This active ingredient dissolved at most only about 5%.
Similarly, a comparative experiment using a capsule of this active ingredient, which is currently commercialized, showed a solubility of only 4.7% after 1 hour. No one could foresee that the composition according to the invention improves the solubility of the active ingredient to this extent (by a factor of about 10).

Example 2 As a lipophilic phase, the melting point was 44.
C., a mixture of saturated C8-C18 polyglycol glycerides having an HLB of 14;
44/14 "was used. This mixture is 52.5% of the total weight of the final composition.

The same composition as in Example 1 was used as the mixture of the surfactant and the auxiliary surfactant. This TA + Co
The weight ratio of the mixture of TA is 35% of the composition, TA / Co
The ratio of TA is 0.5. Also in the second embodiment,
The same characteristics as in Example 1 were confirmed.

Example 3 The same lipophilic phase as in Example 2
Only the same ratio was used. The mixture of surfactant and co-surfactant consisted of the same surfactant as in Examples 1 and 2 but with diglycolethyl, and the applicants assigned "TRAN
This is a combination of auxiliary surfactants commercialized under the trade name of "SCUTOL". This TA + CoTA mixture is 35% of the total weight of the final composition, with a TA / CoTA ratio of 0.5.

Example 4 The same lipophilic phase as in Example 2 was used. This lipophilic phase comprises 73.73% of the total weight of the final composition.
7%. The same mixture of TA + CoTA as in Example 2 is used. The weight ratio of this mixture was 18.5 of the final composition.
In%, the TA / CoTA ratio is 0.5.

Example 5 The same lipophilic phase as in Example 2 is used in the same proportions. The mixture of surfactant and co-surfactant consisted of a polyglycerin oleic ester with an HLB of 10 and was assigned by the applicant to "PLUROL OLEIQUA.
A surfactant commercialized under the trade name "E" and Example 3
And a mixture with the same auxiliary surfactant. The weight ratio of this mixture is 35% of the composition and the TA / CoTA ratio is 1
It is.

FIG. 1 is a pseudo three-component diagram showing the characteristics of this embodiment. In this figure, L indicates a lipophilic phase and H indicates a hydrophilic phase. The range over which microemulsions occur is very wide, and is compatible with high water content (0%
From 60%). Therefore, the composition containing these active ingredients has a very high dilutability, so that an excellent solubilizing effect is obtained in the digestive system, and the bioavailability of the active ingredients is increased. Until now, such excellent results have not been obtained.

Example 6 The lipophilic phase has a melting point of 42.
C., a mixture of saturated C8-C18 polyglycol glycerides having an HLB of 12
A product commercialized under the trade name of "42/12" was used. Using the same surfactant and co-surfactant combination as in Example 1, the lipophilic phase has a melting point of 42 ° C. and an HLB of 12
Of saturated C8-C18 polyglycol glyceride. FIG. 2 is a pseudo three-component diagram showing the characteristics of this embodiment. The range over which microemulsions occur is very wide, corresponding to high water content (0% to 70%).

Example 7 A lipophilic phase having a melting point of 44
C., a mixture of saturated C8-C18 polyglycol glycerides having an HLB of 14;
44/14 "was used. This lipophilic phase accounts for 45.2% of the total weight of the final composition.
It is. As the surfactant TA, the same mixture as in Example 1 was used, and it was 3.7% of the total weight of the composition. As the co-activator, “PLUROL” of the same composition as in Example 5 was used.
The product called "OLEIQUE" was used here as co-surfactant in a proportion of 7.5%. TA / Co
The ratio of TA is 1, and the active ingredient (indomethacin) is 43.5% of the whole.

Example 8 In vivo experiments were performed using indomethacin as an active ingredient in rats. The weight ratio of each component of this mixture is as follows. Surfactant: LABRASOL 44.90% Auxiliary surfactant: PLUROLLEIQUE 15.00% Lipophilic phase: LABRAFIL WL 2609 BS 39.90% Active ingredient: indomethacin 0.20%

First, indomethacin of the above composition was orally ingested. As a result, after one hour, the plasma concentration was 5 to 7 micrograms per milliliter (μg
/ Ml) and after 2 hours from 7 μg / ml to 13 μg
g / ml.

In the second experiment, oral ingestion of powdered indomethacin suspended in situ was performed. One hour later, the plasma concentration was confirmed to be 1 μg / ml to 5 μg / ml, and 2 hours later, it was confirmed to be 1 μg / ml to 4 μg / ml. The reaction rates obtained are irregular and vary from experimental animal to animal. The bioavailability is about twice as good with the intake according to the invention.

Example 9 In this example, the dissolution rates of hydrocortisone in a digestive environment (pH = 1.2) were compared. The same lipophilic phase and the same TA /
The CoTA mixture was used in the following ratios: Hydrocortisone 4.0% Lipophilic phase 19.2% Surfactant 57.6% Cosurfactant 19.2%

As a result of this experiment, the dissolution rate in the living body was 45
The dissolution of the powdered hydrocortisone was found to be 10% in 45 minutes, up to 50% in minutes.

Example 10 In this example, the dissolution rates in a digestive environment (pH = 1.2) where powdery diclofenac sodium hardly dissolves were compared by a biological experiment. The weight ratio of each component of this mixture is as follows. Surfactant: LABRASOL 38.40% Auxiliary surfactant: PLUROLLELIQUE 38.40% Lipophilic phase: LABRAFIL WL 2609 BS 19.20% Active ingredient: diclofenac sodium 4.00%

In this experiment, it was found that the dissolution rate reached 86% in 30 minutes, while the dissolution of the powdered diclofenac sodium was only 1% in the same time.

Example 11 In this example, the dissolution rate of indomethacin alone in a digestive environment (pH = 1.2) showing a dissolution rate of less than 5% was compared by a biological experiment. The weight ratio of each component of this mixture is as follows. Surfactant: LABRASOL 57.60% Auxiliary surfactant: PLUROLLEIQUE 19.20% Lipophilic phase: LABRAFIL WL 2609 BS 19.20% Active ingredient: indomethacin 4.00%

This experiment resulted in a 57.1% dissolution rate in 30 minutes.

Example 12 In this example, the same components as in the above example were used in the following ratios. Surfactant: LABRASOL 43.40% Auxiliary surfactant: PLUROLLELIQUE 14.40% Lipophilic phase: LABRAFIL WL 2609 BS 38.40% Active ingredient: indomethacin 4.00%

From this experiment, a dissolution rate of 90% was obtained in 30 minutes. It was found that increasing the lipophilic phase significantly increased the solubility.

[0051]

As described above, the orally ingestible composition for producing the microemulsion according to the present invention has a number of advantages as compared with the compositions known hitherto. Since no aqueous phase is used, these pharmaceutical compositions can be easily packaged, especially as capsules, soft capsules, tablets or plasters. That is, the present invention is a composition that can be taken orally.

According to the present invention, the range of choices in packaging and ingesting method of a composition for pharmaceutical or cosmetic use is expanded. That is, industrial production of the composition according to the present invention is easy.

[Brief description of the drawings]

FIG. 1 is a pseudo three-component diagram showing the characteristics of Example 5 of the composition according to the present invention.

FIG. 2 is a pseudo three-component diagram showing characteristics of Example 6 of the present invention.

Continuation of the front page (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 9/107

Claims (8)

(57) [Claims] 1. A composition for pharmaceutical or cosmetic use forming a microemulsion, comprising at least an active ingredient, a lipophilic phase composed of a mixture of glyceride and a fatty acid ester, a surfactant (TA), A surfactant (CoTA); and a hydrophilic phase, wherein the lipophilic phase is composed of a mixture of C8 to C18 polyglycol glycerides, and has a hydrophilic-lipophilic balance (HL).
B) is less than 16, and the lipophilic phase is from 1% to 75% of the total weight of the composition, and the surfactant (TA) is from C8 to C10 saturated polyglycol glyceride and polyglycerin olein ester And wherein the co-surfactant (CoTA) is selected from the group consisting of propylene glycol laurin ester, polyglycerin olein ester and diglycol ethyl; / CoTA ratio is from 0.5 to 6, wherein the hydrophilic phase of the final microemulsion is formed after ingestion by biological fluids of the digestive environment, wherein the orally ingestible composition produces a microemulsion Stuff. 2. The orally ingestible composition for producing microemulsions according to claim 1, wherein the polyglycol glycerides of the lipophilic phase are saturated and solid at ambient temperature. 3. The composition of claim 1, wherein the polyglycol glyceride of the lipophilic phase is unsaturated and is liquid at ambient temperature. 4. The composition of claim 1, wherein said mixture of polyglycols and glycerides has an HLB of about 14.
An orally ingestible composition which produces the microemulsion according to any one of the preceding claims. 5. The orally ingestible composition for producing microemulsions according to claim 3, wherein the mixture of polyglycols and glycerides has an HLB of 6 and is liquid at ambient temperature. 6. The composition according to claim 1, wherein the weight ratio of the lipophilic phase is from 50% to 75% of the total weight of the composition.
An orally ingestible composition that produces a microemulsion according to any of the preceding claims. 7. The surfactant (TA) has an HLB of 1
An orally ingestible composition producing a microemulsion according to any of claims 1 to 6, characterized in that it is composed of 0 polyglycerin olein ester. 8. An orally ingestible composition producing a microemulsion according to claim 1, wherein the ratio of TA / CoTA is from 1 to 2.