JPS5934153A - Reagent for gastric juice inspection - Google Patents

Abstract

PURPOSE:To determine acidotic symptom of gastric juice by urinalysis, by administering a gastric juice-inspecting reagent obtained by means of coating a water-soluble vitamin with an acid-soluble film. CONSTITUTION:A titled inspecting reagent is obtained by providing a solid matter containing water-soluble vitamin with an acid-soluble film. When this reagent is administered, the acid-soluble film is dissoved with the gastric juice of a man to be inspected, and water-soluble vitamin, for esample riboflavin, as a model medicine is eluted from powder, fine grain, granule, or tablet, and excreted into urine with the laplse of time. Therefore the acidotic symptom or gastric juice of the man to be inspected can be estimated from excreted amount of the vitamin with time.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a reagent for measuring acid symptoms of gastric juice in animals.

In bioequivalence testing of oral drug formulations.

Knowing in advance the acid symptoms of the gastric juice of the individual animals or animals involved is not only useful when planning and planning the test, but also improves the reliability and accuracy of the test. It has extremely important significance.

Generally, the amount of gastric juice in a person when fasting in the early morning is approximately 2θ to 30y.
It is said that the secretion amount for 7 days is about 2 to 3 liters, and the pH is usually 1 to λ.nl. It is in the range of O. gastric juice p
If H is lower than /B, it is called hyperacidity.

A value higher than 2.theta. is called hypochlorhydria, and a value higher than 3j is called achlorhydria. In addition, according to the Katschkalk (Kats Ch-Ka 1 k) Civil Code, the total acidity of gastric juice is within the range of 3θ to θmEq/71, indicating normal value, exceeding θmEq/1 indicating hyperacidity, and below 3θmEq/71. It is classified as having hypochlorhydria, and the free acidity is about /θ~20 lower than the above values.

As is well known, there are two main methods for measuring acid symptoms of gastric juice: the gastric tube method, which directly collects gastric juice and measures its pH, acidity, etc., and the non-gastric method, which uses non-direct methods that do not require a catheter or the like. There is a gastric tube method. With the gastric tube method, it is possible to accurately obtain all information about gastric juice, including not only pH 1 acidity, but also the amount of gastric juice, color tone, odor, and enzymes. The pain it causes is great. Therefore, for example, measurement using the gastric tube method is most appropriate for testing for gastric diseases, but it is also useful for stratifying the gastric acid symptoms of subjects in bioequivalence studies of oral pharmaceutical preparations as described above. The subject method is preferable. Specifically, this gastric tube method also includes (1) pH telemeter method,
(2) X-ray method (using an X-ray contrast agent as a pH-dependent soluble preparation); (3) pH-dependent soluble capsule method (using a model drug or X-ray contrast agent in a hard capsule that dissolves in a specific pH range); There are two methods: (4) the test drug method, which causes relatively less pain to the subject during measurement than the gastric tube method, and the test drug method is easy to operate. Together with this, it is the most commonly used measurement method.

This test drug method involves administering a specific model drug as an acid-soluble preparation and estimating acid symptoms in the stomach from the amount of the model drug excreted in the urine. It is not possible to use normal acid.

It is possible to classify them into high-acid or low-acid levels.

The conventionally known test drugs used in such test drug methods are all seven model drugs selected from basic compounds such as quinine, azur dyes, methylene blue, or azo dyes, and cation exchange resins or proteins. The concentration of acid in gastric fluid.

It is made so that its solubility changes depending on the amount.

However, the model drugs in these known testing agents are foreign substances to living organisms, and are not preferred for administration to healthy individuals due to their side effects. In addition, in all known test drugs of this type, additives are uniformly added to a specific model drug such as the one mentioned above.

When these mixtures are simply formed into tablets and the tablets pass through the stomach quickly, the solubility in the stomach cannot be said to be sufficient even if sufficient gastric acid is present.

For this reason, it has been difficult to accurately determine the symptoms of acidic gastric juice.

The present invention was proposed in view of the above circumstances, and relates to an improved test drug that can easily and safely measure acid symptoms in the gastric juice of a person or animal.

That is, one gastric juice test drug covered by the present invention is a model drug in which a solid material containing water-soluble vitamins, which are originally nutritional substances, is coated with an acid-soluble film.

First, as a model drug for the test agent of the present invention.

The first condition was that there would be no pharmacological problems when administered to healthy individuals.The second condition was that it would be easy to analyze and quantify in urine or blood, and after careful consideration, we found that water-soluble I found that the vitamins were adequate. Examples of water-soluble vitamins that can be applied to the test agent of the present invention include thiamine, riboflavin, pyridoxal, and ascorbic acid.

Among these, riboflavin can be safely administered to healthy people, and its absorption site is in the upper small intestine.

This type of test q2 is convenient for the purpose;
.

It is particularly suitable because it is easy to analyze, (1) it is excreted mainly as riboflavin in urine, and (2) the pH dependence of dissolution is small.

The test agent of the present invention first contains this water-soluble vitamin in an amount of 7 to 30 mg per dosage unit, preferably j~/! obtained by preparing a solid containing 11 g and then coating the surface with an acid-soluble film. In this case, powders, fine particles, granules or tablets are suitable as solid substances.

Of course, it goes without saying that the powder also contains the bulk water-soluble vitamin powder itself. Especially powder.

In the case of fine particles and granules, since the residence time in the stomach is averaged, more accurate measurement of acid symptoms of gastric juice can be expected, which is advantageous for the purpose of the present invention.

In the production of fine particles, granules, or tablets, various excipients, binders, disintegrants, lubricants, and, if necessary, surfactants are added to water-soluble vitamins, and these are then subjected to, for example, a wet granulation process and/or Alternatively, it may be carried out according to conventional methods such as subjecting it to a tabletting process.

The test agent of the present invention is prepared by applying an acid-soluble film to the thus obtained solid material containing water-soluble vitamins. In this 5,
The acid-soluble film refers to an acid-soluble polymer substance 1 capable of forming a film, such as polyvinyl acetal diethylaminoacetate-I-(?fl'7p13 and below 9, for example, the product name "AEA").
J), dimethylaminoethyl methacrylate-methyl methacrylate-1-copolymer (dissolved pl' below 9), e.g.
t) available as E J) or Nor-Methyl-5
- Vinylpyridine methyl acrylate-methacrylic acid copolymer (dissolution pH below 7 and above 9, e.g. available under the trade name "MPMII-7"), or 2
It includes not only coatings formed mainly from polymers obtained by appropriately mixing these polymeric substances, but also hard capsule coatings made from these polymeric substances. Although it is completely free to specifically select and use the above-mentioned substances or other substances as the acid-soluble substance,9 the dissolution pI (dissolution pI) of the film formed for the purpose of the present invention is at least 3.
It should be adjusted to less than 1A, preferably less than 1Aθ. Note that in the case of the test agent of the present invention, fine particles or granules are coated with such an acid-soluble substance.

There is no hindrance to filling the test drugs into easily soluble hard gelatin capsules in order to facilitate their handling, especially their administration (taking). Therefore, the test agent of the present invention consists of a so-called coating solid obtained by coating the surface of a powder, fine grain, granule, or tablet containing water-soluble vitamins with an acid-soluble substance adjusted to a predetermined dissolution pH, and a so-called coating solid substance obtained by coating the surface of a powder, fine granule, granule, or tablet containing water-soluble vitamins with an acid-soluble substance adjusted to a predetermined dissolution pH. Powder or granules containing previous water-soluble vitamins,
Acid-soluble hard capsules obtained by filling granules or tablets into hard capsules molded from the same acid-soluble substance as above, and further coated powder, fine granules, or granules with the acid-soluble substance are mixed into hard gelatin capsules. These include formulations such as easily soluble hard capsules obtained by filling the moreover.

In the case of these easily soluble hard capsules, two or more types of capsules containing different combinations of PI (and water-soluble vitamins) are mixed in one capsule as appropriate. It is also possible to leave it.

To measure the acid symptoms of gastric juice using the test drug of the present invention9: Take this test drug together with a predetermined amount of water under certain conditions, such as on an empty stomach early in the morning, and then collect urine after a certain period of time has elapsed. Then, the amount of water-soluble vitamins in the urine can be measured.

In other words, if one test drug is taken, the test subject's gastric fluid (
acid).

The acid-soluble film (coating film or capsule film) on the surface dissolves and then the water-soluble vitamin as a model drug is extracted from powder, fine granules, granules or tablets.

For example, riboflavin is eluted and excreted in the urine over time, so the acid symptoms of the subject's gastric juice can be estimated from the amount of vitamin excreted over time. If the subject is acid-free or hypochloremic, the acid-soluble film on the surface of the test drug will not dissolve easily, and the elution of water-soluble vitamins will be insufficient, resulting in extremely low levels of vitamin excretion in the urine. On the other hand, if the subject has orthoacidity or hyperacidity, the acid-soluble film begins to dissolve immediately after taking the second dose, and as a result, the water-soluble vitamins are sufficiently eluted, resulting in a reduction in the amount of vitamins. Urinary excretion appears early and in high concentrations. In this way, the amount of water-soluble vitamins excreted in the urine in the test drug of the present invention is closely correlated with the acid symptoms of the subject's gastric juice. The acid symptoms of gastric juice can be estimated to be acidic, hyperacid, hypoacid, or no acid. in this case.

If two or more test drugs, each with a water-soluble vitamin as a model drug and a different combination of the dissolution pH of its acid-soluble film, are appropriately combined and administered at the same time (of course, if these test drugs are preliminarily administered to seven test drugs), If it is filled in easily soluble hard capsules.

By confirming the type and amount of vitamins excreted in the urine (one capsule is sufficient), a more accurate diagnosis of acid symptoms can be determined.

The determination of water-soluble vitamins in urine is preferably carried out by, for example, high performance liquid chromatography.

For this reason, when performing a gastric juice test using the test drug of the present invention, it is necessary to avoid taking vitamin supplements, etc. in advance, as well as avoid the effects of vitamins derived from the diet. It is best to carry out the test under certain conditions, for example, early in the morning on an empty stomach.

As detailed above, the test agent of the present invention can easily measure gastric acid symptoms in humans (or animals) without causing pain to the subject. In addition, since the test agent of the present invention selectively uses water-soluble vitamins as a model drug,
While conventional test drugs of this kind had some problems when administered to healthy people due to side effects, etc., there are no such concerns at all.

Therefore, the test drug of the present invention is prepared by measuring the gastric acid symptoms of a large number of test subjects (volunteers) in advance, especially before conducting a bioequivalence test of an oral pharmaceutical preparation.

It can be suitably used for the purpose of classifying the state of their gastric juice into acidic, hyperacid, hypoacid, or no-acid groups. In addition, in the case of hard capsules containing acid-soluble substances, it is convenient because a desired water-soluble vitamin can be arbitrarily selected and used as a model drug prior to testing (administration).

The present invention will be explained in more detail with reference to Examples below.

Example/ [Composition of central granules] Riboflavin jθ<y) white
sugar jθθi
・Umorokoshidenbun 22j lactose
2θθ After mixing riboflavin, white sugar, corn starch and lactose according to the above composition ratio,
Spherical granules are produced by the transfer granulation method while gradually adding 300g of n solution. After drying the granules with warm air at θ°C in the evening, they were classified with a sieve to obtain granules having a mesh size of 21I to t2.

The following acid-soluble film coating is performed using this as the central granule.

[Composition of film coating liquid]

Polyvinyl acecool diethylamino acetate /30 (9>talc/glycerin fatty acid ester /1 ethanol
/79 ta Add ethanol to polyvinyl acecool diethylamino acetate according to the above composition ratio, stir and dissolve, then add glycerin fatty acid ester and Kururi,
A coating liquid is prepared by further stirring and mixing.

The previously prepared granules 2θθg containing boflavin were placed in a Uniblat fluidized bed apparatus, and the above-mentioned coating liquid was added to tl,
Coating is carried out by spraying at a speed of g/min and simultaneously blowing JoC air. This operation is carried out for about 2 hours to coat the core granules with an acid-soluble film layer of 7jθg per kg, and then dried by blowing hot air at 0°C for 3θ minutes. /73 rll of this coated granule is filled into No. 2 gelatin hard capsules. The dissolution of boflavin from this preparation in test solutions of various pH was measured using the 10th edition of the Japanese Pharmacopoeia (hereinafter simply referred to as middle circumference) dissolution test method 2 (paddle rotation speed/θθ rpm). The following results were obtained (see Figure 1). Majko, /j, 3 of this preparation
The second change in each dissolution rate due to the pH of the test solution after 60 minutes
As shown in the figure.

Example 2 [Composition of film coach ink liquid] Polyvinyl acetal diethylaminoacetate-1-/! ;θ(g talc jθ polyethylene glycol (-1θθθ) /θethanol
/79θ According to the above composition, ethanol is added to polyvinyl acetal diethylaminoerotate and dissolved with stirring, then polyethylene glycol and talc are added and further mixed with stirring to produce a coating liquid.

The core granules θθg produced in Example/ were placed in a Uniblat fluidized bed apparatus, and the above-mentioned coating liquid was added to 'A9
2j″ into the device while spraying at a speed of /min.
It takes about 6 hours to send air of C and per center granule/kti, 7. ! ;Coat with a film layer of Og. Pack Kono-coated granules/7sWIg into a No. 2 size hard gelatin container. The dissolution properties of this formulation in test solutions of various pHs were measured using the lambda method of the dissolution testing department of a subsidiary, and the following results were obtained.

1 Preparation has “ribo””””””dissolution Example 3 [Composition of core tablet] 1 Flavin λθθ (g)
5 ~ Corn starch.

/ is lactose /, :
2θθ 3θ Hydroxypropyl Lulose
30 073; Magnesium stearate
/θ θ, 23 total 2oθ
θ jθ Mix boflavin, corn starch, and lactose according to the above composition, add 70% solution of hydroxypropyl cellulose 3009, knead, granulate by 1 cylinder extrusion method, dry and crush to a 3θ mesh or less. 9. Next, add 1 g of magnesium stearate to the Mf11n/59xy, mix, and then use a tablet machine to make tablets with a diameter of 3 pxz. This tablet was used as a core tablet and subjected to the following acid-soluble film coating.

Composition of C film coating liquid] Polyvinyl acetal diethylamino acetate / θθ (g) talc Yu θ Polyethylene glycol (+ θ) /θ Ethanol is added to polyvinyl acetal diethylamino acetate according to the above composition ratio.
- Polyethylene glycol (+-Otsu00θ) was added and stirred and dissolved.

Add talc and stir to mix to prepare a coating solution.

7,000 tablets of the previously prepared core tablets were placed in a beer sugar-coated pan with a diameter of 3θθ, and the above-mentioned coating liquid was sprayed for 20 seconds using an automatic spray device.
Dry by blowing warm air at θ°C for 3θ seconds. This operation is repeated for approximately j hours to coat 97 inches of film per tablet.

The disintegration properties of this coated tablet at various pH values were measured using a subdivision disintegration test method, and the following results were obtained.

Example of tablet disintegration [Composition of film coating liquid] Dimethylaminoethyl methacrylate-methyl methacrylate copolymer /θθ (Notalc
/3; Glycerin fatty acid ester
/θ ethanol l
I-G θ meter /θ(/U Dimethylaminoethyl methacrylate-1 according to the above composition
After adding ethanol to the methyl methacrylate copolymer and stirring to dissolve it, talc, glycerin fatty acid ester, and methylene chloride are added and further stirred and mixed to prepare a coating liquid.

7000 tablets of the core tablets produced in Example 3 were placed in a via-shaped sugar-coated pan with a diameter of 3θ0, and the above coating liquid was sprayed for 2θ seconds using an automatic spray device. Blow air for seconds to dry. This operation is repeated for about 5 hours to coat the film layer JJ'■/tablet to obtain an acid-soluble film-coated tablet.

The dissolution properties of this tablet in test solutions of various pHs were measured by Shimin's dissolution test method 2, and the following results were obtained.

Example of dissolution of riboflavin from preparations! The test agent of the present invention manufactured according to Example 1 was actually administered to 39 people, and gastric acid symptoms were measured. The conditions for the measurement are as follows: urinate after waking up early in the morning, collect blank urine immediately before administering the test drug, then take the test drug with 100 g of water, collect urine 2 hours later, and quantify the amount of riboflavin in the urine.

Quantification of urinary riboflavin was performed by high performance liquid chromatography (HPLC) using an absolute calibration curve method. The specific measurement conditions are as follows.

(1) After measuring the volume of pretreated urine, centrifuge several ml of it.
rpm, ,! ; minute) jpl of supernatant liquid to HPLC
Inject into.

(2) HPLC condition column U Bondapak Ctr (70 μm, 3
θtynL.

ggffff1ll Precolumn Bondapak C, Corasil
(/θmmL.

mmID') Mobile phase 007M Genchi P O1//CH,? OH
(Otsu 3; /33) / Prepare I]H5 with N-N a OH.

Flow rate 10m1/min Detector Fluorescence detector Waters model 4'
2θ-E excitation wavelength filter 36Onm Fluorescence wavelength filter 33θnm The results measured by the above method are shown in the table below.

In the upper table of Table 1, those whose urinary riboflavin excretion amount within 2 hours after administration of the °C5 test drug is less than /θO7η are considered to be achlorhydric.

/θθ~3θθ1Jlj can be determined to have hypochlorhydria. This result was consistent with the acid symptoms obtained by separately measuring 20 randomly selected subjects using the gastric tube method.

Looking at the results in Table 1 in terms of the average values by age group of the subjects, it is as shown in Table 2.Furthermore, the measurement results shown in Table 1 indicate that patients with achlorhydria whose urinary riboflavin excretion amount is 700 M/2 hr or less Table 3 shows the incidence rate by age group of subjects, and this also roughly corresponds to the general clinical values.

(Left space below) Table 2 Table 3 Example Otsu No. 2 Size: Apply wax as a release agent to the surface of a bottle (made of metal) for molding hard capsules, and use the bottle to mix polyvinyl acecool diethylamino acetate with 3θ% ethanol. It is immersed in the solution, pulled out, and air-dried for 5 minutes.

After repeating immersion and air drying three times, leave it at room temperature overnight.

Further, the bottle is dried under reduced pressure at 110° C. and approximately /θθyyHg, and the shell of polyvinyl acecool diethylamino acetate formed on the bottle surface is peeled off from the bottle and cut into a certain length. Bottles with slightly different diameters are used to create the capsule body and cap, which are then fitted together to contain two acid-soluble
The number is hard turnip medium.

Next, this capsule was filled with 700 Mg (equivalent to riboflavin j) of the core granules prepared in Example/1 to prepare a test reagent. Various p of this acid-soluble cabbage agent
The dissolution properties in the test liquid were measured using the secondary dissolution test method 2 and the following results were obtained. When we actually administered it to humans under the same conditions as in Example S and measured acid symptoms in the stomach, the results were similar to those for the test drug (coated granules) in Example J and were measured using other gastric tube methods. It matched well with that.

[Brief explanation of drawings]

Figure 1 shows various I)Ts of test drugs obtained in Examples of the present invention.
(Graph showing dissolution of boflavin in test solution, 2nd
The figure is a graph showing the change in the dissolution rate after /3.30.6θ minutes of the same test drug depending on the test solution p■. Applicant National Institutes of Health Shionogi & Co., Ltd. Figure 1 θ 102θ 3θ Guj 60 hours (
) Figure 2 1'l-! ;Otsu 7'f 9H

Claims (7)

[Claims] (1) A gastric juice testing reagent comprising a solid substance containing water-soluble vitamins coated with an acid-soluble film. (2) The gastric juice testing reagent according to claim (1), wherein the solid substance is a powder, fine granules, granules, or tablets. (3) The reagent for gastric juice testing according to claim (1), wherein the acid-soluble film is a coating film made of an acid-soluble substance. (4) The gastric juice testing reagent according to claim (1), wherein the acid-soluble film is a hard capsule made of an acid-soluble substance. (5) The reagent for gastric juice testing according to claim (3), which is filled in a hard ceratin capsule. (6) The reagent for gastric juice testing according to claim (1), (2), (3), (4), or (5), wherein the water-soluble vitamin is riboflavin. (7) The reagent for gastric juice testing according to claim (5), which is a mixture of two or more test reagents having different combinations of dissolved p■ of the acid-soluble film and water-soluble vitamins.