JPH0797338A - Sustained release preparation - Google Patents

Abstract

PURPOSE:To prepare a sustained release preparation easy in production, enabling to control the release-starting time and release period of an active ingredient, and having an excellent sustained release activity. CONSTITUTION:A sustained release preparation is produced by adding (C) a physiologically active substance, e.g. physiologically active peptide such as a peptide related to a calcitonin gene, to a carrier comprising (A) a water-soluble polymer having a cellulose skeleton, e.g. methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, especially hydroxypropylcellulose and (B) a saccharide, preferably lactose or glucose. The components A, B and C are compounded in amounts of 10-90wt.%, 1-40wt.%, and 0.0001-30wt.%, respectively. The preparation is preferable as an internally embedding type sustained release preparation, concretely, an intracerebrally embedding type sustained release preparation, capable of being embedded in vivo to express an effect on a pathologic state for which a therapeutic effect can not be expected by a parenteral administration method, a local administration method, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sustained-release preparation containing a physiologically active peptide in a carrier containing a water-soluble polymer having a cellulose skeleton and a saccharide. In particular, by implanting this preparation in the body, it can be effective in the pathological condition where the therapeutic effect cannot be expected by intravenous administration or local administration. The present invention relates to a sustained release preparation.

[0002]

2. Description of the Related Art Sustained-release preparations that control the elution of a drug in the living body and regulate the absorption when the drug is administered in vivo have been studied for a long time. For example, a method of coating the drug with various coatings, a method of incorporating the drug in a wax or polymer matrix, and the like are known.

In intravenous drug administration for the treatment of intracerebral diseases, the transfer of the drug into the brain is hindered by the blood-brain barrier. In addition, as a method for directly administering a drug into the brain, there is a method in which a catheter is placed at the time of surgery to continuously deliver the drug into the brain, but the device is expensive and the risk of infection is high, so it is reliable. It is hard to say that there is a method.

[0004] Further, in late-onset cerebral vasospasm that occurs after subarachnoid hemorrhage, the pathological condition is delayed and persistent, and therefore, a method of inserting a catheter for drug administration or a method of continuous intravenous administration Is used. However, at present, the method for obtaining a reliable therapeutic effect has not been developed.

[0005]

In such a situation, a drug product in which the drug release start time and the drug release period can be adjusted, for example, drug release is started 1 day or more after administration, and drug release is 5 days or more. A formulation that lasts for a long period of time is preferable in reducing the administration frequency, but it has not existed until now. A sustained-release carrier using chitin and / or chitosan and a carboxyvinyl polymer has been proposed, but this is because a natural product is used as a raw material.
There is a problem that the certainty of procuring raw materials is lacking. The effect also appears about 3 hours after administration and does not last for a day, so it is not sufficient to control the effect. As can be seen from the above circumstances, the sustained-release preparation, in which the raw materials are surely available, can be easily adjusted and has a sufficient sustained-release property, the release start time can be adjusted, and the drug can be released over a long period of time Was desired to be developed.

[0006]

As a result of intensive studies by the present inventors, it was found that the disintegration property of a preparation can be adjusted by incorporating a saccharide into a water-soluble polymer having a cellulose skeleton. By this method, it can be easily prepared and a sufficient sustained release property can be obtained. Moreover, the release initiation time can be adjusted (late or early), and the release of the drug can be continued for more than 10 days. The inventors have found that a formulation that can be obtained is obtained, and completed the present invention.

That is, according to the present invention, 1 is a sustained-release preparation characterized by containing a physiologically active substance in a carrier containing a water-soluble polymer having a cellulose skeleton and a saccharide. 2. The sustained-release preparation according to 1, wherein the physiologically active substance is a physiologically active peptide. 3. The sustained-release preparation according to 2, wherein the physiologically active peptide is a calcitonin gene-related peptide. 4. The sustained-release preparation according to 1, wherein the water-soluble polymer having a cellulose skeleton is hydroxypropyl cellulose. 5. The sustained-release preparation according to 1, wherein the saccharide is lactose. Is obtained.

The water-soluble polymer having a cellulose skeleton used in the present invention includes hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like. Of these, hydroxypropyl cellulose is preferred. The compounding amount is not limited and is determined in consideration of the release start time and the release duration time, but is generally 10% by weight to 90% by weight, preferably 40% by weight to 80% by weight.

As sugars, sucrose, lactose, glucose, fructose, maltose, dextrin, trehalose, pullulan and the like are used. Of these, lactose and glucose are preferable. The disintegration property of the sustained-release preparation can be adjusted by adding a saccharide. That is,
The disintegration rate can be increased by adding a large amount. The compounding amount is not limited, and is also determined in consideration of the release start time and the release duration time, and is generally 1% by weight-
It is 40% by weight, preferably 10% -30% by weight.

The physiologically active substance is not limited at all, and examples thereof include adrenaline, abscisic acid, arginine vasotocin, angiotensinogen, angiotensin, angiotensin I converting enzyme, gastric secretion inhibitory polypeptide, insulin, insulin-like growth factor, S.
Factor, erythropoietin, luteinizing hormone, luteinizing hormone-releasing hormone, luteinizing hormone, oxytocin,
2-octyl-γ-bromoacetoacetate, autacoid, gastrin, gastrin secretagogue peptide, gastron, active vitamin D ₃ , kallidin, calcitonin, urokinase,

Calcitonin gene-related peptide, kininogen, thymus hormone, glucagon, glucocorticoid, vasoactive intestinal peptide, plasma kallikrein, serum factor, blood glucose increasing hormone, thyroid stimulating hormone, thyroid stimulating hormone releasing hormone, thyroid hormone, melanophore Stimulating hormone, melanophore stimulating hormone releasing hormone, melanophore stimulating hormone release suppressing hormone, corticotropin-like middle lobe peptide, cholecystokinin octapeptide,
Cholecystokinin tetrapeptide,

Cholecystokinin variant, cholecystokinin-12, cholecystokinin pancreothymine, cholecystokinin, cell growth factor, substance P, female hormone, adipokinetic hormone, ciliated gonadotropin, nerve growth factor, Pancreatic polypeptide, gonadal stimulant, gonadotropin, growth hormone, growth hormone releasing factor, secretin, cerulein, serotonin, fibroblast growth factor, glandular kallikrein, somatostatin,
Somatomedin A, B, blackening and reddening hormone,

Placental lactogen, thymosin, thymopoietin, thyroglobulin, traumatic acid, endothelial cell growth factor, mollusc cardiac excitatory neuropeptide, neurotensin, pregnant mare serum gonadotropin, brain hormone,
Noradrenaline, vasopressin, estrogen, histamine, epidermal growth factor, parathyroid hormone, parathyroid stimulating hormone, adrenocorticotropic hormone releasing factor, adrenocortical hormone, PACAP, bradykinin, bradykinin-like peptide, proinsulin,

Proopiomelanocortin, prostaglandin, proPTH, prolactin, prolactin-releasing hormone, prolactin-releasing hormone, florigen, menopausal urogenital gonadotropin, bombedin, maxadilan, mineralocorticoid, photoadaptation hormone,
Methionyl lysyl bradykinin, 1-methyl adenine,
Melatonin, motilin, androgen, diuretic hormone,
Lipotropin, renin, relaxin, follicular maturation hormone and the like are used. The blending amount varies depending on the drug used and the purpose of use, but is generally 0.0001% by weight to 30% by weight.
Is.

For formulation, known formulation techniques can be applied. Then, it may be formulated as it is, but conventionally known disintegration regulators, stabilizers, antioxidants, wetting agents, binders,
A lubricant, etc. is added to formulate tablets, pills, capsules, liquids, ointments and the like.

The sustained-release preparation containing a physiologically active substance thus obtained is not only an epoch-making preparation which can be used by implanting it in the body, for example, in the brain, but also conventional oral administration, enteral administration, transdermal administration. It is also used in methods such as administration. Moreover, this sustained-release preparation is characterized by releasing the drug while maintaining the dosage form.

[0017]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples, and improvements that can be made by those skilled in the art are also included in the scope of the present invention. Must understand.

[Example 1] Production of sustained-release preparation (I) 0.4% calcitonin gene-related peptide (CGRP)
2.0 g of solution (equal to 8 mg of CGRP) and lactose 2
Mix 0 g well and add 80 g hydroxypropyl cellulose to it. After thoroughly mixing this, flat tablets having a diameter of 13 mm were produced with a KBr tablet molding machine (150 kg, 1 minute).

[Example 2] Production of sustained-release preparation (II) 0.4% calcitonin gene-related peptide (CGRP)
2.5 g of the solution (equal to 10 mg of CGRP) and 20 g of glucose are mixed well, and 80 g of methyl cellulose is added thereto. After mixing this well, KBr tablet press (1
A flat plate tablet having a diameter of 13 mm was produced at 50 kg for 1 minute.

Example 3 Drug Release Test 5 ml of Hartmann's solution is aseptically placed in a 15 ml tube. Thereafter, the tablets obtained in Example 1 are similarly aseptically put and shaken at 37 ° C. and 120 rpm. 1, 2, 3,
The drug release amount was determined by sampling on days 7, 11, and 14 and quantifying by high performance liquid chromatography. The result is shown in FIG.

The numbers in the figure indicate the disintegrated state of the dosage form, and the meaning thereof is as follows. Disintegration state 1: No change 2: Swelling of 20% is observed 3: Small cracks are present 4: Large cracks are present 5: Shattered

The conditions of high performance liquid chromatography are as follows.

[0023]

[Outer 1]

[0024]

EFFECTS OF THE INVENTION The sustained-release preparation of the present invention, in which a physiologically active substance is mixed with a carrier containing a water-soluble polymer having a cellulose skeleton and a saccharide, is easy to manufacture, and its release initiation time and release period are excellent. It has a sustained release activity.

[Brief description of drawings]

FIG. 1 is a graph showing the% CGRP detection over time of the preparation of Example 1.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 38/00 38/23 47/26 C (72) Inventor Takaaki Baba Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 2-12-1 Shiseido 2nd Research Center (72) Inventor Kazuo Watanabe 2-12-1 Fukuura, Kanazawa-ku, Yokohama, Kanagawa Shiseido 2nd Research Center

Claims (5)

[Claims] 1. A water-soluble polymer having a cellulose skeleton,
A sustained-release preparation characterized in that a carrier containing saccharides contains a physiologically active substance. 2. The sustained-release preparation according to claim 1, wherein the physiologically active substance is a physiologically active peptide. 3. The sustained-release preparation according to claim 2, wherein the physiologically active peptide is a calcitonin gene-related peptide. 4. The sustained-release preparation according to claim 1, wherein the water-soluble polymer having a cellulose skeleton is hydroxypropyl cellulose. 5. The sustained-release preparation according to claim 1, wherein the sugar is lactose.