JPS62111919A - Propranolol pharmaceutical - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, obtained by forming propranolol which is a beta-blocker as an enteric dosage form, capable of enhancing the migration from the stomach to duodenum and keeping the concentration in the duodenum at a remedially effective amount and efficiently treating angina pectoris, arrhythmia, etc. CONSTITUTION:A propranolol pharmaceutical obtained by enteric coating of propranolol [chemical name; 1-isopropylamino-3-(1-napththyloxy)-2-propanol] with an enteric film material, preferably cellulose acetate phthalate and administered as an enteric dosage form. The dosage form is normally tablet, but may be granule or capsule. The case of low absorption ratio in conventional oral administration is not decomposition by gastric acid or metabolism by enterobacteria but caused by slow migration rate from the stomach to the duodenum. The enteric dosage form enhances the blood concentration in the duodenum which is an absorption site and improves the drug effect.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to enteric coated propranolol formulations.

Propranolol is 1-isopropylamino-3-(1
It has the chemical structure of -naphthyloxy)-2-propatool, has the effect of blocking the β-action of adrenaline, and has a bradycardia effect.

It is used to treat arrhythmia, angina pectoris, essential hypertension, etc.

By the way, from the viewpoint of convenience and safety when administering liquid medicines, tablets are commonly used today, but their effectiveness is known to be significantly lower than that of injections, and there are large individual differences. Improvements have been long awaited.

The inventors of the present invention have come up with the above idea and, as a result of various studies, have found that the difficulties can be solved by making propranolol into an enteric-coated dosage form, and have completed the present invention.

The gastrointestinal absorption of propranolol (hereinafter referred to as "1 product") is extremely good, and most of the dose is absorbed, but unfortunately, the absorbed ice crystals are surrounded by the liver before they reach the systemic circulation. It is known that it is excreted from the portal blood. Because of this phenomenon called the "initial pass effect," when administering the two products orally, a dose of ~10 times that of intravenous administration is required; The current situation is that there are large individual differences in the transit effect, making the problem even more complicated.

The present invention conducted the following experiments, believing that elucidation of the above phenomenon is essential for solving problems in oral administration of ice crystals. In other words, in order to kinetically analyze the pharmacokinetics of ice crystals in rabbits due to the remarkable first-pass effect of ice crystals, we first introduced a solution of ice crystals into the stomach, portal vein, and liver of rabbits. The drug was administered into the intestinal vein, etc., and the decomposition of ice crystals by gastric acid and the metabolism of ice crystals by intestinal bacteria were also examined.

As a result of the detailed experiments described above, the cause of the low absorption rate of this product after oral administration of this product is not due to gastric acid decomposition or metabolism by intestinal bacteria, but due to the transfer of ice crystals from the stomach to the fatty intestine. It was found that this was due to the extremely slow rate of absorption.In other words, in oral administration using conventional tablets, the movement of the two products into the duodenum, which is the absorption site, is negligible; It was found that it was difficult to reach and maintain the concentration of the drug to the therapeutically required value.

The reason for the difficulty in oral administration of quartz has thus been clarified, and the next challenge is how to administer quartz to solve this difficulty. Theoretically, administering crystal directly into the duodenum would be most effective, but in actual clinical practice, such a method is impractical due to equipment and equipment requirements. Here, the idea of the present invention is the result of divine consideration.

It was discovered that the intended purpose could be achieved by enteric coating the oral dosage form of quartz.

Entericization in the present invention can be performed by various methods.

This is usually done by applying an enteric coating, that is, a coating that does not dissolve in the stomach but dissolves in the intestines and releases the drug.

Enteric coatings have traditionally been used to prevent gastric irritation of drugs (enzymes, antibiotics, hormones, etc.) that may be degraded or inactivated by gastric juices, and have recently been used to prevent drug action time. It is used in analgesics and sulfa drugs to regulate (sustain and slow release)

However, the method of enteric coating in the present invention is completely different from that in the known drugs as described above. In other words, in view of the fact that oral administration of crystals has traditionally been extremely inefficient in terms of dosage compared to injections, as mentioned above, we searched for the cause and unexpectedly found that it was due to crystal He discovered that the reason for this was that the passage of blood from the stomach to the duodenum was extremely unsatisfactory, and as a result of various studies to find a solution to this problem, he was able to achieve his intended purpose by enteric coating. This is what we discovered.

Therefore, the present invention is not limited to what is known in the art.
Similarities are made to the objects seen, their purpose and function.
The effect is fundamentally different from that in the prior art.

The enteric solution technology applied in the present invention maintains an insoluble state for a relatively long time in the acidic range of gastric fluid (PH1-3.5), and reaches the intestinal fluid (Ii16-7) in a short time. Any material that uses a film or other material that dissolves may be used. As the material for such an enteric coating, various natural, semi-synthetic or synthetic resins are preferably used. The main ones are shellac, wax, cellulose derivatives (such as yalulose acetate phthalate (CAP), cellulose acetate sacrene 1.
(CAS]), polyvinyl compound dibasic monoester (e.g. polyvinyl alcohol phthalate [PVAP
), modified polyvinyl alcohol phthalate rDPVAP
)), maleic acid copolymer (PEMA'), styrene/maleic anhydride copolymer, styrene/maleic acid copolymer, styrene/maleic acid hemiester copolymer),
Examples include methacrylic acid/methacrylic acid ester copolymers (eg, Eudragit (registered trademark)).

How to perform enteric coatings using these materials.

As the material, it is usually preferable to use the materials listed above, including CAP. Although enteric coating is often applied to tablets in this way, it may also be applied to fine granules, fine granules, and other solid dosage forms, if necessary.

In addition, other operations such as sustained release treatment and sustained treatment may be used in combination as appropriate, as long as they do not impede the effects of the present invention. Depending on the case, the above-mentioned enteric-treated granules, fine particles, etc. may be filled into capsules, or the capsule itself may be enteric-coated by, for example, formaldehyde treatment, or if necessary, these may be further added. There is no problem in using them together.

The present invention will be explained in more detail with reference to Examples below. Naturally, the following examples merely illustrate some of the preferred embodiments, and the present invention is by no means limited to these examples.

Example 1 1000 crystal tablets were made according to the following recipe according to the conventional method.

This is subjected to enteric treatment according to a conventional method using the liquid of the prescription ◎ to obtain the tablets of the present invention.

Prescription (c) Propranolol hydrochloride 10f JP
Lactose 561 days corn starch 24 days crystalline cellulose 18 days low hydroxypropyl cellulose g diurnal cycle CMC-N a 2.
4 g own station Mg stearate O,
61 prescription ◎ CAP 10.3 g Macrogol 6000 1.1 f Talc 0.8 da Titanium oxide o, s y Add this to C using a solution of methylene chloride and ethanol (1:1).
The solution is made to have an AP concentration of 8%.

Example 2゜For tablets based on the formulation Ml of Example 1 above, CAP9
, 6y and 1.8 y of triacetin was subjected to enteric coating using a methylene chloride/ethanol (455:450) solution with a CAP concentration of 8%, and this was mixed with 37.6 y of white sugar and 1 y of titanium oxide. The tablets are further sugar-coated with a solution of the above to obtain the tablets of the present invention.

Example 3゜For tablets according to the formulation of Example 1 above, the following formulation◎
The tablets of the present invention are obtained by enteric treatment using a solution obtained by using a conventional method.

Prescription Q Hydroxypropyl methylcellulose phthalate 200
731(i(,P-55) 9,3f
Macrogol 6000 4. ．． 3y Titanium oxide 1.7y This is made into a solution using methylene chloride/ethanol (1:1.5) so that the HP-55 concentration is 7%.

Reference Example Four enteric-coated tablets of the present invention (containing 10 parts of crystal per tablet) prepared according to the formulation of Example 1 are orally administered in a sachet. For comparison, four tablets according to the formulation in Example 11'c, ie, 4 tablets of Group 1 tablets with the same crystal content but without enteric coating, were prepared.

Orally administered to another rabbit. The rabbits used in this experiment were fasted for 24 hours before drug administration and had a body weight of 1.8 to 2.2 kg.
Kq of male Japanese white rabbits were used, with 5 rabbits per group.

Next, blood was collected from the rabbit at regular intervals and the concentration of crystal in the blood was measured. The details are as follows. Sunao]
The rabbit is fixed in the dorsal position, and blood is collected by cannulating the anterior artery with a T-shaped catheter under ether anesthesia. Specifically, 1 to 1.2 ml of blood was collected using a heparin-treated syringe, transferred to a heparin-treated test tube, and then 3
,000 rpm for 5 minutes to collect plasma 51t. This was then followed by the quantitative method of fPshand et al. ((:
eye n, pharmacol Ther, 11,112-1
Spectrofluorescence 4 degrees 1 (manufactured by Shimadzu,
Using type RF-500L (3), excitation wavelength 295n
Quantification was performed under the conditions of m and flowering wavelength of 353 nm.

The results are shown in the attached Figure 1. The solid line 1 is a graph plotting the blood concentration values of those treated with the enteric coating of the present invention, and the broken line is those without such treatment. It can be seen that the blood concentration is approximately twice as high as that of the control.

[Brief explanation of drawings]

FIG. 1 is a comparison diagram of blood concentrations of a preparation according to the present invention and a control preparation. More buds/H]

Claims (1)

[Scope of Claims] (1) Propranolol formulation in enteric-coated dosage form (2)
The formulation of item 1 whose dosage form is a tablet (3) The formulation of item 1 whose dosage form is a granule (4) The formulation of item 1 whose dosage form is a capsule