JPH04356420A - Thiamine-cobalt-chlorophyllin complex compound-containing composition - Google Patents

Abstract

PURPOSE:To obtain the subject composition, improved in bioavailability and excellent in selective coating properties on ulcerated parts and further remarkably improved in color and odor by blending a mono- or a polyhydric alcohol with a substance selected from neutral oils, essential oils and surfactants. CONSTITUTION:A composition is composed of (A) a thiamine-cobalt-chloropyllin complex compound, known to have antiinflammatory, antiulcer action and therapeutic effects on anemia and gastritis and expressed by the formula or its pharmaceutically permissible salt, (B) one or two or more selected from monohydric alcohols (e.g. ethanol or cinnamyl alcohol) and polyhydric alcohols (e.g. glycerol or polyethylene glycol) and (C) one or two or more selected from neutral oils (medium-chain fatty acid triglyceride), essential oils and surfactants, e.g. polyoxyethylene sorbitan ester of a fatty acid and a polyoxyethylene alkyl ether.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to thiamin, cobalt,
A thiamine-cobalt-chlorophyllin complex compound in dissolved form, which has an enhanced peptic ulcer effect and has masked the color and characteristic odor of the chlorophyllin complex compound or a pharmaceutically acceptable salt thereof; Alternatively, the present invention relates to a composition containing a thiamine-cobalt-chlorophyllin complex compound that is once dissolved and then solidified.

0002

[Prior Art] A thiamine-cobalt-chlorophyllin complex compound is a green water-soluble powder and is known to have anti-inflammatory, anti-ulcer, anemia-treating and gastritis-treating effects (Japanese Unexamined Patent Publication No. 47-30825) , Japanese Patent Publication No. 55-133
315, JP-A-57-62281, JP-A-58-4885, JP-A-2-149522).

[0003] In these prior patent publications,
A thiamine-cobalt-chlorophyllin complex compound is dissolved in a monohydric alcohol such as methanol, ethanol, isopropanol, benzyl alcohol, etc. to form a solution (JP-A-47-30825, JP-A-55-13).
No. 3315, JP-A No. 57-62281, JP-A-58-41885) and the disclosure of thiamine-cobalt-chlorophyllin complex compound in polyoxyethylene castor oil, fractionated coconut oil or peanut oil to produce pharmaceuticals. A composition has been disclosed (Japanese Unexamined Patent Publication No. 58-41885).

0004

[Problems to be Solved by the Invention] As mentioned above, the thiamine-cobalt-chlorophyllin complex compound is both water-soluble and fat-soluble. Improving the availability of anti-ulcer agents is recognized as a major challenge, and when used as an anti-ulcer agent, increasing the selective coverage of ulcer sites is necessary to achieve the goal of enhancing drug efficacy. Therefore, there has been a need for a thiamine-cobalt-chlorophyllin complex compound preparation with increased selective coverage.

[0005] Furthermore, since the thiamine-cobalt-chlorophyllin complex compound has a unique deep green color and also has a specific odor, problems such as color masking and odor masking must be solved when formulating this compound. This is raised as an issue.

[0006]

[Means for Solving the Problems] As a result of intensive research to solve the above-mentioned problems, the present inventors have developed a thiamine-cobalt-chlorophyllin complex compound having the following composition, namely (
A) Thiamine-cobalt-chlorophyllin complex compound or a pharmaceutically acceptable salt thereof; (B) one or more substances selected from the group consisting of monohydric and polyhydric alcohols; and (C) neutral oil. A composition containing a thiamine-cobalt-chlorophyllin complex compound, which is composed of one or more substances selected from the group consisting of essential oils and surfactants, has improved bioavailability and can be selectively coated on ulcer sites. The present invention was completed based on the discovery that it is an extremely excellent thiamin-cobalt-chlorophyllin complex compound preparation, which has excellent properties and also has color and odor that are significantly masked.

The thiamine-cobalt-chlorophyllin complex compound and its salt as the component (A) in the composition of the present invention have the following structural formula [I].

Compounds having [Formula 1] and salts thereof, examples of which include salts of mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, alkylbenzenesulfonic acid, and formic acid. , acetic acid, propionic acid,
Salts of organic acids such as succinic acid, butyric acid, valeric acid, oxalic acid, malonic acid, adipic acid, and azelaic acid; salts of amino acids such as glycine, alanine, glutamic acid, and aspartic acid; and alkalis such as Li, Na, and K. Metal and Mg
, salts of alkaline earth metals such as Ca, Ba, salts of organic amines such as dimethylamine, diethylamine, aniline, pyridine, ethanolamine, diethanolamine, and ammonium salts. In the present invention, the above-mentioned thiamine-cobalt-chlorophyllin complex compound and its salt can be used alone or as a mixture of two or more kinds, and when mixing two or more kinds, the mixing ratio is necessary. It can be changed arbitrarily depending on the situation.

[0008] Methods for preparing this thiamine-cobalt-chlorophyllin complex compound are disclosed in JP-A-47-30825, JP-A-48-14617, and JP-A-57-6.
Methods specifically described in JP-A No. 2881, JP-A-58-41885, etc. are used.

[0009] One of the above-mentioned components (B) of the composition of the present invention
Specific examples of alcohols include aliphatic monohydric alcohols such as ethanol, n-propanol, i-propanol, myristyl alcohol, lauryl alcohol, aromatic monohydric alcohols such as cinnamyl alcohol, and mixtures of two or more of these alcohols. . Specific examples of polyhydric alcohols include aliphatic polyhydric alcohols such as glycerin, pentaerythritol, polyethylene glycol, polypropylene glycol, sorbitol, and mixtures of two or more thereof.

[0010] The amount of these alcohols used is 0.1 to 0.1 to thiamine-cobalt-chlorophyllin complex compound.
The amount is 50 parts by weight, preferably 0.5 to 10 parts by weight.

Specific examples of the neutral oil for component (C) of the composition of the present invention include vegetable oils such as soybean oil, corn oil, peanut oil, and cottonseed oil, animal oils such as fish liver oil, and medium-chain fatty acids. Examples include those that are liquid at room temperature, such as triglycerides, and oils that dissolve by heating at low temperatures. Particularly preferred are medium chain fatty acid triglycerides.

Specific examples of essential oils include peppermint oil, anise oil, fennel oil, orange oil, cumin oil, cinnamon oil, cinnamon oil, geranium oil, perilla oil, spearmint oil,
Clove oil, touka oil, rose oil, coconut oil, eucalyptus oil,
Examples include lavender oil and lemon oil.

Specific examples of surfactants include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, polyoxyethylene castor oil diglyceride POE(6) sorbitan monolaurate, and polyoxyethylene sorbitan monolaurate. polyoxyethylene sorbitol fatty acid esters such as polyoxyethylene sorbitol fatty acid esters, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyglycerol fatty acid esters such as decaglyceryl monolaurate, hexaglyceryl monolaurate, polyethylene such as POE (10) monolaurate, etc. Examples include glycol fatty acid esters, polyoxyethylene castor oil, and mixtures of two or more thereof. Among these, those with an HLB of 10 or more are particularly preferred.

Among these neutral oils, essential oils, and surfactants, those that can dissolve the thiamine-cobalt-chlorophyllin complex compound in combination with alcohols are preferred.

[0015] These neutral oils, essential oils, and surfactants have a zero resistance to thiamin-cobalt-chlorophyllin complex compound.
．． It is used in an amount of 0.1 to 20 parts by weight, preferably 0.1 to 10 parts by weight.

The composition of the present invention can be easily prepared by mixing the above-mentioned components in predetermined amounts and stirring the mixture under heating if necessary.

[0017] The preparation containing the composition containing the thiamine-cobalt-chlorophyllin complex compound as an active ingredient obtained in this way has a markedly improved bioavailability as described below, and can be selectively coated on ulcer sites. In addition, it has remarkable effects, such as excellent odor masking and ease of ingestion when administered to humans.

The composition of the thiamine-cobalt-chlorophyllin complex compound thus obtained contains itself and additives necessary for pharmaceuticals, such as antioxidants such as tocopherol and ascorbic acid, sugars, sweeteners such as saccharin, and fragrances. It can be used in the form of a liquid or semi-solid preparation, as a composition with added agents, flavoring agents, coloring agents, etc.

Furthermore, the composition of this thiamine-cobalt-chlorophyllin complex compound can be filled into soft capsules or hard capsules according to a known formulation using any filling machine, if necessary.

[0020] The composition of the thiamine-cobalt-chlorophyllin complex compound of the present invention will be specifically explained below with reference to Examples and Experimental Examples.

In this example, thiamine cobalt chlorophyllin represented by the structural formula [I] was used as a specific example, but the present invention is not limited to the use of this compound, and the salt of [I] This can be applied to all complex compounds containing

Example 1 Soft capsule (Formulation I)
Compound [I]
10mg
Polyethylene glycol 400
150mg decaglyceryl monolaurate
40mg 10g Thiamine Cobalt
Chlorophyllin complex compound [I] and 150 g of polyethylene glycol 400 are mixed and stirred while heating to about 60°C. When [I] is dissolved, 40 g of decaglyceryl monolaurate is added and further stirred to obtain a clear green liquid.

[0023] An amount equivalent to 10 mg of [I] was taken from this liquid and filled into soft capsules.

Example 2 Soft capsule (formulation II)
Compound [I]
20mg
glycerin
100mg
Polyoxyethylene sorbitan monooleate 130 mg 100 g of glycerin is added to 20 g of thiamine-cobalt-chlorophyllin complex compound [I], and the mixture is stirred while being heated to about 60°C. When [I] is dissolved, 130 g of polyoxyethylene sorbitan monooleate is added and further stirred to obtain a clear green liquid.

[0025] An amount equivalent to 20 mg of [I] was taken from this liquid and filled into soft capsules.

Example 3 Soft capsule (formulation III)
Compound [I]
10mg
ethanol
20m
g Glycerin
15
0mg medium chain fatty acid triglyceride (MC
T) Add 20 g of ethanol to 120 mg (10 g) of thiamine-cobalt-chlorophyllin complex compound [I] and dissolve it, then add 150 g of glycerin and stir the mixture while heating it at about 60°C. When [I] has completely become a solution, 120 g of MCT that has been heated to 60° C. is added and stirred well to form a uniform green liquid substance.

[0027] An amount equivalent to 10 mg of [I] was taken from this liquid and filled into soft capsules.

Example 4 Semi-solid formulation (formulation IV) Compound [I]
20mg
Polyethylene glycol 1500
260mg Polyoxyethylene sorbitan monooleate 120mg1g
Thiamine-cobalt-chlorophyllin complex compound [I]
to 13g of polyethylene glycol 1500 at about 75℃
After dissolving by heating, 6 g of polyoxyethylene sorbitan monooleate was added and stirred.

[0029] This liquid was cooled and made into a powder, or in the form of a solution, the equivalent of 20 mg of thiamine-cobalt-chlorophyllin complex compound [I] was filled into hard capsules.

Example 5 Solid formulation (formulation V) Compound [I]

5mg polyethylene glycol 400
40mg
Polyethylene glycol 4000
100mg peppermint oil

After dissolving 5mg1g of thiamine-cobalt-chlorophyllin complex compound [I] in 8g of polyethylene glycol 400 by heating at about 65°, 20g of flaky polyethylene glycol 40
00 and 1 g of peppermint oil were added and mixed, and the resulting solid preparation was filled into hard capsules.

Example 6 Solid Formulation (Formulation VI) Compound [I]

10mg polyethylene glycol 4
00 (PEG400) 90mg
Medium chain fatty acid triglyceride (MCT)
50mg sorbitan monolaurate
50mg polyethylene glycol 6000 (PEG6000)
After adding 90 g of PEG400 to 100 mg and 10 g of thiamine-cobalt-chlorophyllin complex compound [I] and dissolving it, MCT and sorbitan monolaurate were added and heated at 65°C. Separately, 100 g of PEG 6000 was dissolved and added to form a uniform suspension, which was then filled into hard capsules.

[0032] It was confirmed that the formulations of Examples 1 to 6 were stable for more than 6 months with no change in content and maintaining the shape at the time of manufacture.

[0033] The above formulations are reference examples, and the present invention is not limited thereto.

Test Example 1 (Ulcer site covering effect) In order to examine the ability of the thiamine-cobalt-chlorophyllin complex compound to cover ulcer sites, acetic acid ulcer model rats were prepared. Acetic acid ulcers are diagnosed under ether anesthesia under the serosa of the body of the stomach.
It was prepared by injecting 50 μl of 15% acetic acid.

Seven days after the production of an acetic acid ulcer, the distribution of the thiamine-cobalt-chlorophyllin complex compound to the ulcer site was examined.

[0036] Animals fasted overnight were given thiamine, cobalt,
Aqueous solution of chlorophyllin complex compound (TCC) (TCC
30mg/5ml/kg) and the same amount of PEG400 liquid (T
CC 30 mg/5 ml/kg) was orally administered to a group of 5 rats, and 1 hour later they were sacrificed and their stomachs were removed.

[0037] The extracted stomach was incised from the greater curvature side, washed lightly with physiological saline, and a 1 cm2 section including the ulcerated area was excised. Furthermore, a part symmetrical to the lesion was cut out in the same area as a normal part.

[0038] After homogenizing both parts, thiamin.
Extract the cobalt-chlorophyllin complex compound and perform HPLC
The amount of coating per 1 cm2 was calculated using the following.

Improvement in ulcer site coverage (acetic acid ulcer model rat)
・30mg/kg TCC (6mg/m1 head)
・Fasting ・Concentration: 1 x 1 cm2 Solvent Normal site Ulcer site Distilled water
64.55±36.44 59.57±3
3.03 PEG400 51.58±1
6.28 123.63±78.73

(n=3,μ
g±S. E. )

Test Example 2 (Bioavailability) The soft capsule prepared in Experiment Example 1 and the thiamine-cobalt-chlorophyllin lactose diluted product (control) were administered to beagle dogs fasted for 24 hours.
mg equivalent is administered orally with 40 ml of water.

[0041] After administration, 30 minutes, 1 hour, 1.5 hours, 2
Blood was collected from the forelimb vein at 4 hours, 6 hours, 8 hours, and 10 hours, and the amount of thiamin, cobalt, and chlorophyllin in the plasma was measured using the HPLC method.

AUC(ng・h/
m1) Tmax (h) Cmax (ng/
ml) T1/2(h) Control
226 2.0
37.5 2.8 Prescription I 397 1.5
57.4 3.0

0043
]

Effects of the Invention It has been revealed that the composition containing the thiamine-cobalt-chlorophyllin complex selectively coats the acetic acid ulcer site in rats, and has a covering power more than twice that of a normal site.

Furthermore, the rate of absorption from the gastrointestinal tract was also found to be significantly increased compared to solid preparations, suggesting that it contributes to an increase in local blood flow in the stomach.

From the above, it was confirmed that the composition of the present invention has the effect of enhancing the efficacy of the thiamine-cobalt-chlorophyllin complex compound.

Claims (1)

[Claims] Claim 1: (A) a thiamine-cobalt-chlorophyllin complex compound or a pharmaceutically acceptable salt thereof;
(B) One or more substances selected from the group consisting of monohydric and polyhydric alcohols, and (C) One or two substances selected from the group consisting of neutral oils, essential oils, and surfactants. A composition containing a thiamine-cobalt-chlorophyllin complex compound consisting of the above.