JP3123100B2 - Absorption promoter - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an absorption promoter containing a compound having cyclopentacycloheptene as a basic skeleton (hereinafter referred to as "azulene compound") as an active ingredient.

[0002] Here, as the azulene compound, for example,
Examples include guaiazulene, kamaazulene, azulene sulfonate, azuretyl salt, and the like. Examples of the azulene sulfonic acid salt include pharmacologically acceptable salts of azulene sulfonic acid, such as sodium azulene sulphonate and potassium azulene sulphonate.
Examples of azuretyl salts include pharmacologically acceptable salts of azuretyl acid, such as azuretyl sodium and azuretyl potassium.

[0003]

2. Description of the Related Art In recent years, in addition to or instead of conventional administration methods such as oral administration, injection, etc., the number of administrations has been reduced, side effects such as gastrointestinal disorders have been avoided, sex differences have been reduced, individual differences have been reduced. Absorbs drugs from the nasal, oral, or rectal mucosa (hereinafter simply referred to as "mucosa") and skin for the purpose of easy dosage control, improved compliance, reduced burden on patients, and avoidance of drug addiction Dosing regimens are attracting attention.

[0004] However, the mucous membrane and the skin, particularly the skin, originally have a role of preventing the invasion of foreign substances, and the mucous membrane is not necessarily in a form for actively absorbing the drug. It is often difficult to achieve sufficient absorption from the skin. In particular, water-soluble drugs are much more difficult to absorb from mucous membranes and skin than fat-soluble drugs because mucous membranes and skin are fatty tissues. It is generally said that those having a low molecular weight are more easily absorbed than those having a high molecular weight. Furthermore, even if it is absorbed, a sufficient amount of absorption may not be obtained, or it may take time to reach an effective amount.

[0005] For this reason, attempts have conventionally been made to convert a drug into a prodrug to enhance fat solubility, physically apply ultrasonic waves, or add various absorption promoters.

[0006] Since the prodrug formation is often difficult depending on the type of drug, a method of adding an absorption enhancer has been well studied, and some absorption enhancers have been found so far. Have been.

[0007] Relatively well studied medium chain fatty acids (Nishimura et al., Chem. Pharm. Bull., 33 (1), 282-291 (1985).
Etc.), sodium caprate has been put to practical use as an absorption enhancer in rectal mucosa.

However, bile salts (Hirai et al., Diabet
es, 27 (3), 296-299 (1978).) and other absorption enhancers require further investigation and improvement for irritation of mucous membranes and skin.

Azulene compounds are widely used in the form of ointments, granules, tablets, etc. for use as anti-inflammatory agents, anti-ulcer agents, etc., as seen in sodium azulene sulfonate and guaiazulene. It is already known as a drug with little irritation to the skin. However, it is not known at all whether or not it has an absorption promoting action.

[0010]

Under the circumstances described above, the present inventors have shown an absorption-promoting effect especially on water-soluble drugs, and reached an effective amount in a relatively short time, and furthermore, applied mucosa. And to provide an absorption enhancer with little irritation to the skin.

[0011]

Means for Solving the Problems In order to achieve the above object, the present inventors screened a large number of compounds, and fortunately found that an azulene compound, which is a component of plant chamomile, has an absorption promoting effect. The present inventors have completed the present invention because they have little irritation to mucous membranes and skin.

The present inventors have first confirmed by the present invention that an azulene compound has such an absorption promoting action.

Accordingly, the gist of the present invention is an absorption promoter containing an azulene compound as an active ingredient.

Hereinafter, the absorption enhancer according to the present invention (hereinafter, referred to as "the present accelerator") will be described in detail.

The accelerating agent of the present invention can be prepared by using an azulene compound as it is or by using water, ethanol, propylene glycol or the like.
It can be used by dissolving, dispersing or suspending it in one or more suitable solvents.

The accelerator of the present invention may be used in combination with a suitable excipient, an antioxidant and the like.

The accelerator of the present invention may be used in combination with another compound having an absorption promoting action, if necessary, for synergistic effects and the like.

For example, medium-chain fatty acids and salts thereof such as capric acid, caprylic acid and lauric acid; medium-chain fatty acid glycerides such as caprylic acid monoglyceride; medium-chain fatty acid esters such as isopropyl myristate and isopropyl palmitate; sodium taurocholate; Bile salts such as sodium glycocholate, cyclodextrins such as α-cyclodextrin, anti-inflammatory substances such as salicylic acid, pyrrolidones such as N-methylpyrrolidone, dimethyl sulfoxide, and polar solvents such as N, N-dimethylformamide. And Azone (registered trademark).

As a method of using the accelerator of the present invention, an effective amount of the accelerator of the present invention is generally used in a preparation containing a drug whose absorption is to be promoted (hereinafter referred to as “main drug”). However, it is also possible to use it in a form excluding the main drug. That is, as the pretreatment before the administration of the main drug, the accelerator of the present invention itself or a preparation containing the accelerator of the present invention can be administered.

When the accelerator of the present invention is incorporated into a water-soluble base, when the water-soluble accelerator of the present invention such as azulene sulfonate is incorporated into an oleaginous base, a fat-soluble agent such as guaiazulene is used. Suitably, the accelerator of the present invention is used.

The concentration of the accelerator of the present invention in the preparation varies depending on the site of application, the condition of the patient, the type of the preparation, the additives, the type of the main drug, the concentration of the main drug, and the like. 0.1 to 10% (w / w
%, The same applies hereinafter), and when the accelerator of the present invention is mixed with an aqueous solution or an aqueous gel base, an appropriate concentration of the azulene compound is about 1%. If it is less than 0.1%, a sufficient absorption promoting effect cannot be expected, but it can be used. Also, it is sufficiently possible to mix 10% or more.

Formulations which can contain the accelerator of the present invention include:
The main drug is absorbed by applying to mucous membranes or skin, and many external preparations expected to have pharmacological effects, for example, external preparations, liquid sprays, lotions, tinctures, ointments,
Examples include creams, liniments, gels, sols, aerosols, cataplasms, plasters, tapes, patches, plasters, etc., and rectal preparations such as suppositories, tablets, powders, capsules, granules. Agent, troche, buccal,
Oral administration agents such as solutions, syrups and drops can also be mentioned.

The following can be used for oral administration:
This is because the promoter of the present invention can also promote absorption of gastrointestinal mucosa.

The site of application of the preparation of the present invention may include intranasal, oral, rectal, gastrointestinal, skin and the like.

The drug (drug) that the accelerator of the present invention promotes absorption is not particularly limited, such as a water-soluble drug and a fat-soluble drug, but is particularly effective for a water-soluble but poorly fat-soluble drug, It is also effective for drugs with large

For example, the above-mentioned drugs include polypeptides, proteins and the like.

More specifically, posterior pituitary hormones such as insulin, calcitonins, vasopressin and oxytocin, thyrotropin-releasing hormone, (3R, 6R)-
6-methyl-5-oxo-3-thiomorpholinylcarbonyl-
L-histidyl-L-prolinamide tetrahydrate ((3R, 6R)-
6-methyl-5-oxo-thiomorpholinylcarbonyl-L-histidyl-
Thyrotropin-releasing hormone derivatives such as L-prolinamide tetrahydrate), hypothalamic or release-suppressing hormones such as luteinizing hormone-releasing hormone, somatostatin, opioid peptides such as endorphins and related peptides, vasoactive intestinal polypeptides, neurokinin , Glucagons, calcitonin gene-related peptide, neurotensin, atrial natriuretic peptide, angiotensin, cerebral enteric hormones such as insulin-like growth factor and epidermal growth factor, thymic hormones and thymic hormone-active fragments such as thymocalcine, thymopentin and thymotrinin, Examples include endothelin, platelet activating factor, growth hormone, colony stimulating factor, interferons, tumor necrosis factor, and the like.

[0028]

EXAMPLES The absorption promoting effect of the accelerator of the present invention will be described below in more detail with reference to test examples.

Test Example 1 Insulin 100 U / ml and sodium azulene sulfonate 0
20 μL of an aqueous solution containing 1.5% to 1.5% (L is liter, the same applies hereinafter) is injected into the nasal cavity of a Wistar male rat weighing about 200 g.
U / kg body weight was administered, blood was collected at set time intervals, and plasma insulin concentration was measured.

FIG. 1 shows the results.

When sodium azulene sulfonate did not coexist, almost no absorption was observed.
Absorption was promoted when 5% coexisted.

Test Example 2 Insulin 2 U / kg body weight was administered intravenously, 1% sodium azulene sulfonate aqueous solution was administered nasally alone, insulin 10 U / kg body weight was administered nasally alone, Insulin absorption rate when a 100 U / ml aqueous solution of insulin containing 10% sodium azulene sulfonate was intranasally administered at 10 U / kg body weight was obtained from Formula 1, and the reduction rate of blood glucose level was obtained from Formula 2 and shown in Table 1. .

[0033]

(Equation 1)

Nasal: Insulin n U / kg Area under the plasma concentration time curve from 0 to 4 hours after nasal administration of insulin (h · mU / ml) Control: 0 to insulin without insulin
Area under the plasma concentration time curve up to 4 hours (h · mU / ml
Intravenous injection: 0 U of insulin at intravenous injection of 2 U / kg of insulin
Area under the plasma concentration-time curve up to 4 hours (h · mU / m
l)

[0035]

(Equation 2)

Nasal: 0 of blood glucose level when nasal insulin was administered
Area under the blood concentration time curve up to 4 hours (h · mg / dl
) Control: Area under the blood concentration time curve from 0 to 4 hours of blood glucose level without insulin administration (h · mg / dl) Intravenous injection: From 0 to 4 hours of blood glucose level after intravenous injection of insulin Area under the blood concentration-time curve (h · mg / dl)

[0037]

[Table 1]

In the case of intranasal administration of insulin alone, the absorption rate is 3.
The absorption rate was 66%, but the addition of 1% sodium azulene sulfonate increased the absorption rate to 23.75%, about 6.5 times that of nasal administration alone.

Also, the blood sugar reduction rate is 44.25%,
The improvement was about 3.2 times that of the single administration.

Test Example 3 Salmon calcitonin (100 U / ml) and 10 to 12 μL of an aqueous solution containing 1% of sodium azulene sulfonate were added to a 5-week-old body weight of about 100 to 12
1 U / 100 g body weight was administered into the nasal cavity of 0 g SD male rats, and blood was collected at set time intervals to measure serum calcium concentration.

FIG. 2 shows the results as relative values of the serum calcium concentration.

Compared with calcitonin administration alone, in the presence of sodium azulene sulfonate, a decrease in serum calcium concentration close to that when 10 to 12 μL (1 U / 100 g body weight) of salmon calcitonin was intramuscularly injected was observed. The effect of calcitonin on nasal mucosal absorption was indirectly proved by using the substance of the present invention.

Test Example 4 When 100 U / ml salmon calcitonin was administered nasally or intramuscularly at 10 U / kg body weight alone, a 100 U / ml aqueous solution of salmon calcitonin containing 1% sodium azulene sulfonate was added at 10 U / kg.
In the case of intranasal administration of body weight, the absorption rate of each salmon calcitonin when intranasal administration of 10 U / kg body weight of a 100 U / ml aqueous solution of salmon calcitonin containing 1% sodium caprate was calculated from the calcium concentration in serum from Formula 3. , And Table 2.

[0044]

(Equation 3)

Nasal: 0 to nasal administration of salmon calcitonin
Area under serum calcium concentration curve up to 4 hours (%
h) Control: Area under serum calcium concentration curve from 0 to 4 hours without salmon calcitonin administration (% · h) Intramuscular: Serum from 0 to 4 hours after intramuscular injection of salmon calcitonin Area under the calcium concentration curve (% · h)

[0046]

[Table 2]

Although the absorption rate of salmon calcitonin administered alone was 8.89%, the combined use of 1% sodium azulene sulfonate increased it to 95.16%, about 10.7 times that of the administration alone, and showed that the intramuscular administration Almost comparable.

Also, sodium azulene sulfonate is
Sodium caprate, known as an absorption enhancer,
Although the absorption rate was slightly lower than 99.25% when used in combination with 1%, it had an approximately the same accelerating effect as sodium caprate.

[Brief description of the drawings]

FIG. 1 shows the effect of the concentration of sodium azulene sulfonate on the plasma insulin concentration after intranasal administration of insulin at 10 U / kg body weight (n = 3 to 4). The horizontal axis is time (hours), and the vertical axis is plasma insulin concentration (mU / ml)
Represents each. ○ is 0%, △ is 0.5%, □ is 1%,
◆ represents a change in plasma insulin concentration in the presence of 1.5% sodium azulene sulfonate.

FIG. 2 shows the effect of sodium azulene sulfonate on serum calcium concentration after administration of 10 U / kg body weight of salmon calcitonin. (N = 3) The horizontal axis is time (hour)
The vertical axis represents the relative value (%) of the serum calcium concentration. ○ indicates the case of intranasal administration of salmon calcitonin alone, □ indicates the case of intramuscular administration of salmon calcitonin, and △ indicates the case of intranasal administration of 1% sodium azulene sulfonate-salmon calcitonin.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 9/08 A61K 38/00 A61K 47/06 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] An azulene sulfonate, guaiazulene,
An absorption enhancer for mucosal adaptation, comprising as an active ingredient a compound selected from the group consisting of kama azulene and azuretyl salt .