JPH04149126A - Pharmaceutical composition for transmucous administration - Google Patents

Abstract

PURPOSE:To provide the subject composition containing a peptide-type medicine such as calcitonin and insulin and natural bile extract powder, having high absorbability, giving little irritation to mucosa and having high safety. CONSTITUTION:The subject composition contains a peptide-type medicine and natural bile extract powder (e.g. bile powder, ox bile extract powder, concentrated ox bile, ox bile, liver extract powder and bile extract). The bile extract powder has remarkable absorption promoting effect on the hardly absorbable peptidetype medicine in transmucous administration and gives little irritation to the mucosa. The bile extract powder may be used singly or as a mixture with a surfactant and its amount is preferably 0.1-10mg per unit body weight. It can be prepared in any dosage form suitable for transmucous administration, e.g. tablet, powder, liquid, suppository, ointment or troche. It is absorbed through mucous membrane of nose, oral cavity, rectum, eye, vagina, digestive tracts, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a pharmaceutical composition for transmucosal administration containing a peptide drug and a powdered bile extract of natural origin.

More specifically, the present invention relates to a pharmaceutical composition for transmucosal administration that improves the absorption and bioavailability of peptide-based drugs that have low bioavailability due to poor absorption.

(Problems to be solved by the prior art and the invention) When a drug is administered to a living body, the blood concentration of the drug is determined by the rate and amount of the drug entering the living body (bioavailability), The rate and amount at which the substance is removed by the living body (clearance)
Determined by Therefore, it is always desired to increase the bioavailability of drugs because it increases the blood concentration, leading to improved drug efficacy or reduced dosage.

However, due to their large molecular weight, peptide drugs are not absorbed through the mucous membranes of the gastrointestinal tract, nose, eyes, oral cavity, vagina, etc., or even if they are absorbed, they are degraded by proteases in the mucous membranes. It is known that it is extremely difficult to absorb. As a result, it is difficult to obtain a sufficiently high bioavailability, and conventionally, in such cases, improvement measures have been taken, such as combining insulin with a chymotrypsin inhibitor, or coating the peptide with an abouaromatic copolymer to suppress the degradation of the peptide in the gastrointestinal tract. It has been known.

However, there are drawbacks such as safety issues due to the use of drugs that are not approved as pharmaceutical additives, and the time and effort required for formulation, which makes them impractical. In addition, cationic, anionic, amphoteric, and other ionic surfactants, nonionic surfactants, and bile acids (salts) are known as absorption enhancers for peptide drugs, but these are also used in large amounts. At present, it cannot be put into practical use due to problems in formulation due to the drug and safety problems such as irritation to mucous membranes. Therefore, it has been desired to develop a peptide preparation that has good absorption, high bioavailability, and fewer side effects.

(Means for Solving the Problems) As a result of intensive studies to solve these problems, the present inventors found that, compared to bile salts whose usefulness has been reported in many cases, naturally derived bile extracts The present invention was completed based on the discovery that a very small amount of peptide-based drugs has a remarkable absorption-promoting effect on transmucosal administration of difficult-to-absorb peptide drugs, and has less irritating effect on mucous membranes. Ta.

That is, the gist of the present invention resides in a pharmaceutical composition for transmucosal administration, which is characterized by containing a peptide drug and a powdered bile extract of natural origin.

Hereinafter, the present invention will be explained in detail.

Specifically, the peptide drugs used in the present invention include insulin, calcitonin, and the like.

However, basically any peptide drug that is not absorbed or is extremely difficult to absorb when administered transmucosally may be used, and is not limited to the above specific examples.

The bile extract powder used in the composition of the present invention is a component extracted from natural bile, and specifically includes, for example, bile powder, ox bile extract powder, thick beef tallow, beef tallow, animal fat, yukun, Examples include animal bile extract, liver extract powder, bile extract, and carp bile powder.

Bile extract powder may be used alone or as a mixture with a surfactant.

Examples of surfactants that can be used include fatty acids, fatty acid salts, ionic or nonionic surfactants, phospholipids such as lecithin and hydrogenated lecithin, or cholesterols, with fatty acids or fatty acid salts being preferred.

The amount of bile extract powder mixed varies depending on the type of crude drug, but
Usually 0.1 to 20 cm per unit weight, more preferably 0
．． It is best to use 1 to 10 ■. Other surfactants can be used in appropriate amounts for the bile extract powder.

The administration site of the composition of the present invention may basically be any site that has a mucous membrane in the living body, and administration for the purpose of absorbing the drug through the mucous membrane is called transmucosal administration. Define. Specific examples include the nose, oral cavity, rectum, eyes, vagina, and gastrointestinal mucosa.

Incidentally, small amounts of stabilizers, pH adjusters, flavoring agents, coloring agents, fragrances, preservatives, etc. can be added to the composition of the present invention in the same manner as in ordinary pharmaceuticals according to methods known per se.

The pharmaceutical composition of the present invention may be in a solid or liquid form, such as powder,
Examples include mixed micelle solutions and emulsion solutions. The mixed micelle solution or emulsion solution may be administered transmucosally as it is, but it may also be made into a solid form by removing water by freeze-drying, spray-drying, or the like.

The dosage form may be any suitable for transmucosal administration, such as tablets, powders, liquids, half tablets, ointments, and troches. Since these preparations allow transmucosal administration of peptide drugs conventionally used as injections, they reduce pain and vascular disorders associated with injections, and are also useful for simplifying operations.

The dosage of the composition of the present invention varies depending on the type of active drug, so it cannot be determined unconditionally, but it is usually per adult.

The composition of the present invention can be prepared to contain 50 to 1000 units of herbal medicine and administered transmucosally once to several times a day.

(Example) Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to the following examples unless it exceeds the gist thereof.

Example 1 500 U of [Asu'.7]-chicken calcitonin and bovine albumin (manufactured by Sigma) were added to 5 mf2 of physiological saline.
5 ■ was dissolved, and further 20 ■ of ox bile extract powder (manufactured by Shin Nippon Pharmaceutical Co., Ltd.) was dissolved. The same solution was heated for 1 hour using an ultrasonic device (Tomy Seiko UD-201 model, 20KHz, 200W).
A clear homogeneous solution was obtained (Formulation 1).

Control Example 1 (A s u”) - 500 U of chicken calcitonin and 5 µm of fresh albumin were added to physiological saline, and the total amount was 5 mf.
and the same solution was shaken to obtain a homogeneous solution (control agent 1)
.

Example 2 CAS u”] -, -watricalcitonin 500U
, ox bile extract powder 15mg, sodium linoleate 20
A transparent homogeneous mixed micelle solution was obtained according to the preparation method of Example 1 (Formulation 2) using 5 μg of albumin and 5 μg of albumin.

Control example 2 [As u1'7]-Chicken calcitonin 500U,
Sodium glycocholate 20mg and raw albumin 5
(2) was added to physiological saline to make a total volume of 5 ml, and the solution was subjected to ultrasonication at 20 KHz for 3 minutes to obtain a homogeneous solution (Control Agent 2).

Example 3 i: As u”)-chicken calcitonin 500 U,
Add 20cm of ox bile extract powder, 100cm of sodium caprate (manufactured by Tokyo Kasei Co., Ltd.), and 5cm of bovine albumin to physiological saline for a total of 5 cal! Closed. The same solution was heated at 20KHz.
A uniform mixed micelle solution was obtained by ultrasonication for 3 minutes (Formulation 3).

Control Example 3 (Asu"') - Add 500 U of chicken calcitonin and 5 μ of raw albumin to physiological saline to make a total volume of 5 m12, and shake the solution to obtain a homogeneous transparent solution. Control Agent 3
-1). In addition, (Asu"3 chicken calcitonin 50
0 U, 100 mg of sodium caprate, and 5 μm of raw albumin were added to physiological saline to make a total volume of 5 mff, and the solution was sonicated at 20 KH2 for 3 minutes to obtain a homogeneous solution (Control 3-2). .

Example 4 (As u"7) - 180 U of Watri calcitonin and 10 μ of ox bile extract powder were added to distilled water to make a total volume of 2 ml, and the solution was shaken to obtain a transparent homogeneous solution (Formulation 4)
.

Control Example 4 According to the method of Example 4, 180 U of (Asu'.7)chicken calcitonin was used to obtain a transparent homogeneous solution (Control Agent 4).

Example 5 In 5 ml of distilled water, 20 μl of [A S u ”]-Nichick Calcitoenin 500LI ox bile extract powder and 5 μl of bovine albumin were dissolved. In addition, 100 μl of Mannitol (manufactured by Kao Corporation) was dissolved in the same solution. (2) was dissolved to form a homogeneous solution.The solution was immediately frozen in a dry ice/methanol mixed solution, and gradually dried over 12 hours under reduced pressure using a freeze dryer (Model DC-35, manufactured by Yamato). Removes moisture from
A flocculent powder composition with a pale yellow color was dried (Formulation 5).
).

Example 6 Formulation 5 obtained in Example 5 was filled into miniature capsules (manufactured by Nippon Elanco), and further dipping was performed using HP-50 (manufactured by Shin-Etsu Chemical), which is a type of enteric base. (Formulation 6).

The absorbability of the compositions of the present invention is demonstrated by the following test examples.

Test Example 1 Male Wistar rats fasted overnight (average weight 12
0g) Formulation 1 or 2 (0.5 mE/kg body weight) was administered rectally to each group of 5 animals using a syringe with a probe, and immediately after administration, to prevent leakage of the drug,
The anus was closed using surgical adhesive Aron Alpha [F].

Immediately before and after administering the drug 0.51.1.1,5.
At a total of 7 points at 2.3 and 4 hours, a hematocrit tube containing heparin sodium was injected from the tail vein at 100 μl per time. Blood was drawn. Another 1200
Centrifugation was performed at Orpm for 5 minutes, the plasma was collected, and the calcium concentration in the plasma was determined by the 0CPC method (Calcium C test, manufactured by Wako Pure Chemical Industries, Ltd.), and the amount of absorbed calcitonin was measured to determine the decrease in the concentration of lucium in the plasma. It was evaluated based on effectiveness. That is,
It can be seen that the lower the plasma lucium concentration, the greater the amount of calcitonin absorbed. Incidentally, as a control, the same test was also conducted for the aforementioned Control Agents 1 and 2.

The results are as shown in FIG. 1, and a significant decrease in blood calcium concentration was observed in Formulation 1 containing ox bile extract powder compared to Control 1 which did not contain ox bile extract powder. Furthermore, even when compared with Control Agent 2, which contains sodium glycocholate, which is a type of bile salt, as an absorption enhancer, Formulation 1 has a significant blood calcium lowering effect. Furthermore, in Formulation 2 containing ox bile extract powder and sodium linoleate, a significant decrease in blood calcium concentration was observed over a long period of time. Therefore, it is clear that the absorption of calcitonin in the rectal mucosa is significantly improved by adding a small amount of ox bile extract powder.

Test Example 2 Male Wistar rats fasted overnight (average weight 12
0 g) A group of 5 animals were anesthetized with ether, the upper abdomen was opened for about 2 CT [l], the duodenum was removed, and the preparation 3
0.5mI! ,/kg body weight, and was promptly administered into the duodenum using a syringe with a 28G needle.

After administration, the abdomen was opened using clips to prevent a drop in body temperature and loss of physical strength. Incidentally, as a control, the same test was conducted for the control agent 3 as well. Absorption of calcitonin in the duodenal mucosa was evaluated by measuring blood calcium concentration according to the method of Test Example 1 above.

The results are as shown in FIG. 2, and Formulation 3 of the present invention is different from Control Form 31 which does not contain an absorption enhancer, as well as Control Form 3 which contains only sodium caprate, which is known as an absorption enhancer. It can be seen that blood calcium concentration is significantly reduced when compared with -2. Therefore, it is clear that the composition of the present invention containing ox bile extract powder provides a significant calcitonin absorption pathway in the duodenal mucosa.

Test Example 3 New Sealant White male rabbit fasted overnight (
A group of three birds (average weight 3 kg) was treated with Preparation 4 at 0.
A nasal drop of 1 mff/wing was administered to one nasal cavity. Incidentally, as a control, the same test was conducted for the control agent 4 as well. The absorbability of calcitonin in the nasal mucosa was evaluated by measuring the blood calcium concentration according to the method of Test Example 1 above. The results are as shown in FIG. 3, and Formulation 4 containing ox bile extract powder lowers blood calcium concentration compared to Control Agent 4 that does not contain ox bile extract powder. Therefore, the composition of the present invention It is clear that it increases the amount of calcitonin absorbed by the nasal mucosa.

(Effects of the Invention) According to the present invention, a composition for transmucosal administration that has better absorption and less mucosal irritation than conventional peptide-based drugs can be obtained. Medicines are provided.

[Brief explanation of the drawing]

FIG. 1, FIG. 2, and FIG. 3 are diagrams showing changes in blood calcium concentration over time. The vertical axis in each figure represents blood calcium concentration (■/d1), and the horizontal axis represents time (hour
). In Figure 1, the ○ plot represents the case of Control Agent 1, the △ plot represents the case of Control Agent 2, the Mbrosoto case represents the case of Formulation 1, and the ■
The plots are for Formulation 2, respectively. In FIG. 2, the ○ plot shows the case of Control Agent 3-1, the Δ plot shows the case of Control Agent 3-2, and the * plot shows the case of Formulation 3. In FIG. 3, the ○ plot shows the case of Control Agent 4, and the - plot shows the case of Formulation 4.

Claims (2)

[Claims] (1) A pharmaceutical composition for transmucosal administration characterized by containing a peptide drug and a naturally derived bile extract powder (2) The composition according to claim 1, wherein the peptide drug is calcitonin or insulin.