JPS62500866A - Antidiuretic 1-deamino-8-D-arginine-vasopressin and antidiuretic method - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Antidiuretic 1-deamino-8-D-arginine-vasobrenone and antidiuretic method The present invention generally relates to antidiuretic formulations and methods of treating humans with the formulations. especially books The invention relates to the antidiuretic compound 1-deamino-8-D, commonly known as DDAVP. -Relating to arginine-vasoble, /n.

DI) AVP has high and specific antidiuretic activity and is disclosed in US Patent No. 3.49. It is useful for the treatment of insipidus as published in No. 7,491.

Proteins such as DDAVP and peptides are virtually inhaled in the stomach and intestinal tract. It has traditionally been accepted that they are not collected and are disassembled. Thus, Bepeti Drugs and protein-based drugs have traditionally been administered through the skin or nasal or oral mucosa. It has been administered by absorption from The above mentioned US Patent No. 3,497.491 discloses that DDAVP can be administered subcutaneously or intranasally.

1) Currently, the most common dosage form for administering DAVP is IJnyl (rhnyle). ) requires the use of Linil is rated positive. administered Aspirate the appropriate amount of solution into this tube. Put one end into your nostril and the other end into your nostril. Ru. The contents of the tube can then be placed into the nose. This method of administration is Patients especially elderly! It is difficult to implement for people with ε. Moreover, nasal administration on the contrary affects fine hair and Viruses and bacteria can easily reach the mucous membranes.

In addition, DDAVP is stable in a dry state, but when used in a solution state, the solution is Must be refrigerated and preservatives must be added.

DDAVP solutions can also be administered from a conventional pump spray. 62-500866 (2). However, the dose is <n reliable with this device. do not have. And when the contents reach the bottom of the bottle, there is a considerable amount of waste. So-called There are also problems with the Shudo tablets. This is because it takes time to dissolve and relies on the saliva secretion of children. This is because it exists.

Improved DDAVP formulations suitable for oral administration to humans for gastrointestinal administration Research into the administration and methods of these formulations has continued.

Object of the invention and its summary The general object of the invention is therefore to avoid the problems of the state of the art mentioned above and is essentially in mitigation.

A more particular object of the invention is to provide a single dose formulation of DDAVP after oral administration. It's in the country.

Another object of the present invention is to provide a solution to the gastrointestinal tract in order to enable gastrointestinal absorption of DDAVP. The objective is to provide a DI)AVP formulation that dissolves in DI).

Yet another object of the invention is to provide stable The present invention provides a DAVP formulation.

Another object of the invention is to provide a method for orally administering DDAVP.

Another object of the present invention is to provide a method for orally administering DI) A, VP in total and easily. It is in providing the law.

Still further objects and advantages of the invention are described in the following summary and preferred embodiments of the invention. It will become clear from the explanation.

The present invention provides, on the one hand, diuretic compositions in oral doses for human use. This composition comprises an antidiuretic effective agent and a pharmaceutically acceptable carrier. This formulation The substance can be dissolved and absorbed in the human gastrointestinal tract.

On the other hand, the present invention provides a treatment for insipidus. This method shows that DDAVP has no adverse effects on humans. The method consists of orally administering a urinary effective amount. That DDAVP is human It is dissolved in the gastrointestinal tract and absorbed.

Description of preferred embodiments The antidiuretic effect of DDAVP used in the present invention is entirely due to the absorption of DAVP molecules. It seems likely that Because any peptide in DDAVP by the enzyme Does disassembly of bonds and disulfisothobridges inevitably lead to physiological inactivation? It is et al. In the present invention, the administration of DDAVP used to initiate antidiuretic properties is Oral doses may be used nasally in patients with insipidus to control polyuria. It is only slightly higher than the amount of DDAV.

In the formulations of the present invention, an antidiuretic effective dose of DDAVP in oral dosage form is provided. k can be used. This amount is typically given per 70 kg adult body weight per oral dose. from about 50 to about 200, preferably from about 50 to about 100 micrograms of DDA It is VP.

This oral dosage unit should be taken 2-3 times a day.

This formulation can be used in all dosage forms for oral administration, i.e. tablets, capsules or as described by those skilled in the art. Other known dosage forms may be used.

Tablets are preferred.

Other such formulations familiar to those skilled in the art can be used. Those ingredients are well known Contains fillers and inert components of the pond.

The present invention will be further explained by the following examples and comparative examples.

Examples 1 and 2 Two tablets were made with the following ingredients.

Ingredients Example 1 Example 2 DDAVP (synthesized by Fehring AB) (+ags) 50 to.

Manitol USPXX (mgs) 39 78 Lactose (ph, Eur, II) (mgs) 60 60 microcrystalline cellulose (mgs) 60 80 cro Gas combination CMC (mgs) 2 2 talc (ph, Eur, In) (mgs) 8 8 Magnesium stearate (ph, Eur, I [[) (mgs) 2 2 Microcrystalline cellulose AVICEL PHIOI is from FMC in Philadelphia It is a special product of well-refined cellulose commercially available from Co., Ltd. Also cross knot The crystal CMC is Ac-DI7Sol sodium, which is also commercially available from FMC. It is carboxymethyl cellulose.

Moreover, a small liter of polyvinylpyrroline-ethanol is used as a binder to make the TT agent. It is used as.

The tablets were administered to three patients suffering from insipidus.

Administration was carried out for a period of over 3 months. Necessary to keep enuria in these patients under control The recommended dosage h1 is 2-3 100 mg tablets per 24 hours. No side effects observed There wasn't. Patients prefer tablet administration to DDAVP rather than the usual σ administration. It was.

Comparative example The effects of orally administered DDAVP were compared with orally administered 1-deamino-4-aspa Effect of lagin-8-D-arginine-vanpressin (4-Asn-DDAVP) It was compared as follows.

DDAVP and 4-Asn 1) DAVP to healthy people of both sexes between the ages of 18 and 43. administered.

1 to 2 hours after a normal breakfast, drink an amount of water equivalent to 2% of your body weight. I did it. Collect urine every 15 minutes and measure its BL and permeability using a high-grade permeability meter 3D11. was measured. In order to over-ingest water, the amount of urine equivalent to the amount of urine collected must be I replaced that loss by drinking tap water. After about 40-45 minutes, urination started at 15 minutes. It increased to about 20,011. 20-200 micrograms of DI)A during that period. VP or 4-Agn-DDAVP was administered orally in 50 g of distilled water. . DDAVP and 4-Asn -1) DAVP is easily soluble in water due to Felling AB. Supplied in lyophilized powder form. Water urination was continued for up to 6 hours.

Two of the patients were administered through the nose using a tonidenal tube. The tip of the tube is exposed to X-rays. It was placed in the distal part of the duodenum with help. After collecting water and collecting urine, This was done as described above.

Urine exceeding 200 ml per 15 minutes is due to endogenous secretion of vanpressin or extremely suppressed This can be seen as a sign that something is happening. After that, 200 micrograms of DDAVP The solution was dissolved in 10 ml of water and injected through the tube.

These studies focused on two aspects: the magnitude of the response and the durability (at least 6 hours of effect). An engraving showing that there is a dose-dependent effect of DDAVP (no change in content) ing. Therapeutic effects were achieved at microgram doses of DDAVP. D.D.A. Patients who received Vp via the duodenal tube.

Urine osmolality and conductivity had a direct antidiuretic response when a corresponding increase in ) was observed.

More than just a slight feeling of tension in the stomach associated with the initial water overhydration (overdose) No external side effects were experienced by any of the patients.

Unlike the above results with DDAVP, 4-Agn-DDAVP is 20- When administered orally in a dose of 200 micrograms.

Mild and very short-lived effects occurred only at higher doses.

Moreover, no therapeutic effect was observed at the 100 microgram dose.

The principles, preferred embodiments, and operating methods of the present invention have been described above. However, this The inventions to be protected under this law should be considered to be limited to special inventions that have been made public. It's not possible.

This is because they are not limited, but are for explanation and should be imitated. This is because. Modifications and alterations may occur to those skilled in the art without departing from the spirit of the invention. may be carried out.

Brief description of the drawing Procedural amendment (formality) January 1987

Claims (7)

[Claims] (1) Antidiuretic effect amount and amount of 1-deamino-8-D-arginine-vasobrecin that the formulation is soluble and compatible with the human gastrointestinal tract; An oral antidiuretic composition for human use, which is absorbable in a tube. (2) The composition of claim 1, wherein the composition is in the form of a tablet. (3) The composition of claim 1, wherein the composition is in the form of a tablet. (4) Dose of 1-deamino-8-D-arginine-vasobrecin per dose and 50-200 micrograms per 70 kilogram person. Composition of Box 1. (5) Dose of 1-deamino-8-D-arginine-vasobrecin per dose 50-200 micrograms per person per 70 kilograms The composition of Range 4. (6) 1-deamino-8-D-arginine-vasobrescin is present in the human gastrointestinal tract. 1-deamino-8- in an antidiuretic effective amount so that it is substantially soluble and absorbable. Urinary insipidus resulting from oral administration of D-arginine-vasobrecin to humans treatment for the disease. (7) Amount of 1-deamino-8-D-arginine-vasobrecin per dose Patent: about 50 to about 100 micrograms per 70 kilograms per person The method according to claim 6.