JPH07258078A - Gastrointestinal tract absorption type prolonged nitroglycerin preparation and use thereof - Google Patents

Abstract

PURPOSE:To obtain the preparation useful not only for angina pectoris but also spastic anemia, etc., having excellent absorption from a gastrointestinal tract and stable and durable action, comprising a carrier containing hydroxypropyl cellulose and pullulan. CONSTITUTION:This gastrointestinal tract absorption type duct nitroglycerin preparation comprises (A) a carrier for a preparation contains (B) lactose, (C) hydroxypropyl cellulose and (D) pullulan. The blended amount of nitroglycerin is an amount smaller than 10wt.%. The component A has a particle size distribution of about 60 mesh. The blended amounts are 5-70-wt.% of the component B, 10-80wt.% of the component C and 10-80wt.% of the component D. The viscosity of the component C in 2wt.% aqueous resistance at 20 deg.C is preferably adjusted to 3.0-4,000cp, preferably 150-4,000cp.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a nitroglycerin (hereinafter sometimes referred to as "GTN") preparation, and more particularly to a gastrointestinal absorption-type sustained nitroglycerin preparation and its use.

[0002]

2. Description of the Related Art GTN has long been used as a therapeutic agent for angina because it has a strong dilating effect on the peripheral arteries, but it is necessary to consider urgency and avoid liver degradability Therefore, the applicant company and the like have proposed and implemented devises in administration methods and dosage forms such as transdermal, intranasal, intratracheal, and oral mucosal adhesion administration (Patent No. 1426358,
No. 1461669, Japanese Patent Laid-Open No. 1-117825, No. 4-10
3531 gazette, utility model registration Nos. 1913421 and 191342
No. 7).

For oral GTN preparations, buccal agents for the purpose of absorption through the oral mucosa have been generally used for a long time, and they are a sustained-release base for controlling release and a base for improving dissolution and absorption. The applicant's company has proposed the use of the results of research on drugs, inclusivity agents (suppression of tingling sensation), etc. (JP-A-63-205301,
63-3108117, JP-A-5-163140, etc.).

Further, GTN for absorption from the gastrointestinal tract
Formulations have problems in terms of urgent adaptability, degradability and irritability of GTN, and research on adsorbing GTN with hydroxyalkyl celluloses (Japanese Patent Publication No. 56-9490).
No. 58-17445), but it cannot be said that the problem regarding sustained absorption has been sufficiently solved, and a satisfactory formulation has not been put on the market.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have paid attention to the vasodilatory action of GTN other than the action of dilating the arterial arteries, and have hitherto been able to improve the transplantation rate at the time of skin transplantation, the cerebral circulation improving action,
We have obtained information on hair growth promoting action, anti-impotence action, peripheral vascular disorder ameliorating action, and effective action against frostbite.GTN also has an effect on dilating coronary arteries when used in connection with these diseases. Since there is a strong risk of causing various cardiovascular disorders, it was necessary to limit treatment to angina patients because of this side effect.

[0006] In addition, GTN preparations for treating angina, which are intended to be absorbed from the gastrointestinal tract, can withstand urgent application, have no hepatic degradability, exhibit an action in a short time after administration, and are stable. It was thought that it was difficult to develop a product in which GTN has a persistent effect and does not cause discomfort such as abdominal irritation and bloating.

[0007]

Means and Actions for Solving the Problems In order to solve the above-mentioned problems that the GTN preparations according to the prior art have, that is, in addition to treating and treating angina, the present inventors Even for the GTN preparations that can be used for the preventive or therapeutic purposes for the above-mentioned various diseases and for the treatment of angina, the preparations are well absorbed from the gastrointestinal tract, and the action is stable and continuous. I have been devoted to research to develop a certain formulation. As a result, surprisingly, lactose as a carrier for the formulation,
It was found that a gastrointestinal absorption-type nitroglycerin preparation using hydroxypropylcellulose (hereinafter sometimes referred to as “HPC”) and pullulan is suitable.

This GTN preparation is not only used for the treatment of angina by modifying the GTN content, etc., but also for other purposes, for example, as a preventive and therapeutic agent for diseases caused by vascular disorders, especially as a convulsive agent. The present invention has been completed by finding that it can be safely and effectively used as a preventive and ameliorating agent for ischemic diseases, especially muscle spasms and gastric spasms, even if the patients to be administered are not angina patients. That is, for the purpose of treating angina, for example, a preparation containing GTN at 10 mg / tablet is administered, and for the purpose of preventing or treating other diseases, in order to suppress the cyclic arterial dilation effect of GTN, 1-
A formulation containing several mg / tablet is administered.

Therefore, the gastrointestinal absorption-type sustained-release nitroglycerin preparation according to the present invention is characterized in that the carrier for the preparation contains lactose, hydroxypropylcellulose and pullulan.

In this GNT preparation according to the present invention, the content of nitroglycerin does not exceed 10% by weight, the carrier for the preparation has (1) a particle size distribution of about 60 mesh, and (2) lactose. The blending amount is adjusted to be 5-70% by weight, the hydroxypropylcellulose blending amount is 10-80% by weight, and the pullulan blending amount is 10-80% by weight, and (3) the hydroxypropylcellulose viscosity is adjusted. , 2% aqueous solution and 20 ° C., 3.0 to 4000 cp, preferably 150 to 400 cp.

Among the carriers in the GTN preparation of the present invention, lactose is added for the purpose of stabilizing expression of the pharmacological activity of GTN and the purpose of serving as an excipient.
One part was used to disperse GTN, and the lactose polyploid of this GTN was blended with the remaining lactose and other ingredients and formulated, and HPC and pullulan were used for the purpose of sustained release of GTN. Is compounded in. In formulating, naturally, a lubricant such as magnesium stearate and calcium stearate, a fluidizing agent such as silicic acid anhydride and the like may be added.

[0012]

EXAMPLES The present invention will be described in more detail and specifically with reference to Production Examples, Comparative Production Examples and Test Examples. Production Example The formulation shown in Tables 1 and 2 below, and after GTN was dispersed in lactose, mixed with other components, and then added to "Japanese Pharmacopoeia".
Seven types of tablets were manufactured in accordance with the general rules for formulation and tablets.
In the table below and the table below, the viscosity value of HPC is 2%.
It is a value under the condition of an aqueous solution and 20 ° C.

[0013]

[Table 1]

[0014]

[Table 2]

Comparative Production Example In the formulations shown in Table 3 below and in Comparative Productions 1 and 2, GTN was dispersed in lactose, and in Comparative Preparation 3, HPC was dispersed in the formulation and then mixed with various components, Three types of tablets were manufactured in accordance with the “Japanese Pharmacopoeia” formulation general rules, tablets section.

[0016]

[Table 3]

Test Example 1 (Evaluation of drug release characteristics and stability) For each preparation obtained in Production Example and Comparative Production Example, G
The release characteristics and stability of TN were investigated. For the evaluation of the release characteristics of drugs, "Japanese Pharmacopoeia" general test method, dissolution test method,
It was done according to the paddle method. However, the rotation speed of the paddle is 100
The rpm and the test solution were 500 ml of the Japanese Pharmacopoeia general test method, the disintegration test method, and the second solution of the disintegration test solution. or,
The quantification of the test liquid was performed by measuring by the "Japanese Pharmacopoeia" general test method and liquid chromatography method. The stability was evaluated by storing each formulation at 80 ° C for 0 and 3 days,
It was carried out by measuring its content by the "Japanese Pharmacopoeia" general test method and liquid chromatography method.

The results are shown in Tables 4 to 6 below, and it was found that the preparations of the production examples are far superior to the preparations of the comparative production example in the sustained release property and storage stability of GTN. did.

[0019]

[Table 4]

[0020]

[Table 5]

[0021]

[Table 6]

Test Example 2 (Animal Experiment) A swimming test was carried out by using 8 week-old SD male rats in a group of 5 rats. Two hours before the start of the test, the test group was forcibly orally administered with any of the preparations 1-7 according to the production example, and the control group was forcibly orally administered with any of the comparison preparations 1-3 according to the comparative production example, and the mixture was treated with warm water. Put it in and find the average value of swimming time,
When the test group and the control group were compared, a prolongation effect at a swimming time of 12 ± 4% was observed in the test group. This is
It is shown that the preparation according to the present invention has an action of suppressing convulsions caused by muscle fatigue due to swimming.

Test Example 3 (Human Use Test) Formulation 1 according to the Production Example was administered to 3 volunteers with motor muscle pain.
(Volunteer jumps up to about 300 m, which caused muscle pain the next day) and one volunteer who was apt to develop gastric cramps during cold sensation. (1m as GTN
g) For the gastroconvulsive voluntea with cold sensation, the patient was asked to take one tablet as an uncontrolled drug at the time of occurrence, and a questionnaire survey was conducted on the improvement status of convulsive pain and side effects. The results are shown in Tables 7 and 8 below. No side effects were observed, and all responded that they could expect efficacy.

[0024]

[Table 7]

[0025]

[Table 8]

[0026]

INDUSTRIAL APPLICABILITY The gastrointestinal absorption-type sustained-release nitroglycerin preparation according to the present invention makes it possible to limit the arteriolar dilation effect, which has been well known for GTN, to a necessary minimum. As a result, it is expected to be used not only for the treatment of angina but also for its application at the time of skin transplantation, improvement of cerebral circulation, promotion of hair growth, improvement of peripheral vascular injury, and treatment of frostbite without being limited to angina patients. . Furthermore, since this preparation has a long-lasting property, it is possible to utilize it for the prevention and treatment of convulsive ischemic diseases, especially muscular convulsions, gastric convulsions, etc. as a novel therapeutic effect. The present invention provides.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 47/26 Z 47/36 C 47/38 C // (A61K 47/36 47:38 47: 26) (72) Inventor Zenmi Tsurumi, 35, Higashi Sotobori-cho, Higashi-ku, Nagoya City, Sanwa Chemical Research Institute Co., Ltd.

Claims (3)

[Claims] 1. A gastrointestinal absorption-type sustained nitroglycerin preparation, characterized in that the carrier for the preparation contains lactose, hydroxypropyl cellulose and pullulan. 2. The content of nitroglycerin is 10% by weight.
(1) The particle size distribution is below 60 mesh, (2) Lactose content is 5-70% by weight, and hydroxypropylcellulose content is 10-80% by weight. % And pullulan are adjusted to 10 to 80% by weight, and (3) the viscosity of hydroxypropylcellulose is 3.0 to 4000 cp under the conditions of 2% aqueous solution and 20 ° C, preferably 150%. -The gastrointestinal absorption-type sustained-release nitroglycerin preparation according to claim 1, which is adjusted to a range of 400 cp. 3. A method for preventing and ameliorating convulsive ischemic diseases, particularly muscular convulsions and gastric convulsions, which comprises using the gastrointestinal absorption-type continuous nitroglycerin preparation according to claim 1 or 2.