JPH09278670A - Pharmaceutical preparation for peroral administration of insulinlike growth factor 1 - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical preparation for the peroral administration, comprising an insulinlike growth factor 1 (IGF-1) and capable of simply manifesting sufficient pharmacodynamic effects. SOLUTION: This pharmaceutical preparation for peroral administration comprises an IGF-1 and further a usually used medicinal carrier, more preferably a substance having absorbefacient actions on the IGF-1 (e.g. a surfactant) and/or a substance having suppressing actions on the hydrolysis of the IGF-1 (e.g. casein which is a protectant for protein hydrolysis). The IGF-1 can be formulated as a pharmaceutical preparation for the peroral administration such as a tablet, a capsule, a powder, a fine granule, a liquid pharmaceutical preparation or a liposome pharmaceutical preparation suitable for absorption from an alimentary canal according to a conventional method. The substance having absorbefacient actions on the IGF-1 and/or the substance having suppressing actions on the hydrolysis thereof is blended at 0.1-100 weight ratio to the IGF-1. The daily dose thereof for an adult is about 1-5000mg protein expressed in terms of the IGF-1 administered in one or divided portions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a preparation of insulin-like growth factor 1 (hereinafter referred to as IGF-1) in a novel dosage form, that is, a preparation for oral administration.

[0002]

IGF-1 is an insulin-like peptide existing in blood, which has a growth promoting action on various cells, and its production and secretion depend on growth hormone. In recent years, this IGF-1 has been
Since it can be produced relatively easily and has a growth promoting action, it is a therapeutic agent for pituitary dwarfism, and as a growth promoting agent for short stature, it has a chondrocyte proliferative action and thus a preventive and therapeutic agent for osteoporosis. , Or as a therapeutic agent for bone fracture, it is known to be used as a therapeutic agent for diabetes due to its insulin-like action, and as a therapeutic agent for ulcers, trauma, burns, etc. due to its anabolic action.

[0003]

Conventionally, in the treatment using IGF-1, administration by injection has been carried out,
For example, treatment of diabetes often requires administration of a drug for almost the whole life, and administration by injection imposes a great burden on doctors and patients. It is generally known that bioactive polypeptides are degraded by proteolytic enzymes in the digestive juice, and that absorption from the digestive tract is not sufficient, and the absorption rate is generally 1% or less. Is. IGF-1 is also reported to be degraded by proteolytic enzymes in the digestive fluid in the same manner as such physiologically active polypeptides [eg, J. Endocrinol. (1995) 14
6, 215-225]. Therefore, it is a common general knowledge of those skilled in the art that oral administration of IGF-1 is conventionally unsuitable.
An object of the present invention is to provide an IGF-1 preparation in a dosage form that is simple and capable of absorbing a sufficient amount of IGF-1 to exert a drug effect.

[0004]

In order to solve the above problems, the present inventor has conducted extensive studies and found that IGF-
1 was superior to other physiologically active polypeptides in absorption from the digestive tract such as stomach and intestinal tract, and was first discovered to be suitable for oral administration. As a result of various studies, the present invention was completed.

The present invention is an oral administration preparation containing IGF-1, particularly an oral administration preparation containing IGF-1 and a pharmaceutically acceptable carrier. Preferably, the present invention is the above-mentioned oral administration preparation, which further contains at least one of a substance having an IGF-1 absorption promoting action and a substance having an IGF-1 degradation inhibiting action.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION IGF-1 used in the present invention
For example, gene recombination technology (for example, Japanese Patent Laid-Open No. 61-13
96), IGF derived from mammals such as humans and cows produced by peptide synthesis method, cell culture method and the like.
-1, and further includes a mutant protein having an IGF-1 activity produced by gene recombination technology or the like, in which a part of the amino acid sequence of IGF-1 has an amino acid inserted, substituted, impossible or deleted. Be done.

IGF-1 can be prepared for oral administration using any conventional formulation method. Examples of the oral administration preparation of the present invention include solid preparations such as tablets, capsules, powders and fine granules, liquid preparations, liposome preparations and the like. The formulation is prepared by a conventional means using any necessary pharmaceutical carriers, excipients and other pharmaceutically acceptable additives. Desirably, the formulation is provided in a form suitable for absorption from the gastrointestinal tract. Orally administered tablets, granules, capsules and the like include binders such as syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone and the like; excipients such as lactose, corn starch, calcium phosphate, sorbit and glycine; lubricants , Magnesium stearate, talc, polyethylene glycol, silica and the like; disintegrants such as potato starch and the like; or acceptable wetting agents such as sodium lauryl sulphate and the like. The tablets are preferably coated with an enteric coating known per se in a manner well known in the art.

Oral liquid formulations are aqueous or oily suspensions,
It may be a solution, syrup, elixir or the like. Such liquid formulations include commonly used additives such as suspending agents such as sorbit syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats and the like; emulsifiers. , Lecithin, sorbitan monooleate, acacia, etc .; non-aqueous vehicles such as almond oil,
Fractionation Coconut oil, oily ester, propylene glycol, ethanol and the like; preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and sorbic acid may be contained. Oral formulations may also be solid formulations which are dissolved in water or other suitable vehicle before use.

Liposomes are closed vesicles having an inner aqueous phase portion surrounded by a lipid bilayer formed by dispersing lipids in water, and have a multiconcentric bilayer, single layer or multilayer structure. It has the ability to take in physiologically active substances such as various proteins into the spaces.

The lipid used for the production of liposomes may be any lipid that is physiologically acceptable and metabolizable, and examples thereof include phospholipids, glycolipids and derivatized lipids. Examples of the phospholipid include phosphatidylcholine, phosphatidylserine, phosphatidic acid, phosphatidylglycerin, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, dicetylphosphate, and their inclusions, that is, soybean phospholipids and egg yolk phospholipids.

Examples of the glycolipid include cerebroside, sulfidide, ganglioside and the like. Examples of the derivative lipid include cholic acid and deoxycholic acid.

As a method for producing liposomes, for example, a freeze-thaw method (Pick U .: Arch. Biochem. Biophys., 21 2, 186) is used.
(1986)), ultrasonic treatment (Huang, C .: Biochemistry,
8, 344 (1969)), surfactant treatment method (Brunner, J. et a
l .: Biochim. Biophys. Acta, 455 , 322 (1976)), reverse phase evaporation method (Szoka, F. et al .: Proc. Natl. Acad. Sc
i .: USA, 75 , 4194 (1978)), emulsifier method (Talsm
a, H. et al .: DrugDev. and Ind. Pharmacy, 15 , 19
7 (1989)) and the like.

The oral preparation of the present invention may contain a substance having an IGF-1 absorption promoting action or an IGF-1 decomposition inhibiting action. The substance having an action of promoting the absorption of IGF-1 may be any substance capable of promoting the absorption of IGF-1 in the body, for example, a nonionic surfactant,
Examples thereof include anionic surfactants, cationic surfactants, amphoteric surfactants and surfactants such as bile acids, mineral oils, lipophilic substances such as triglycerides, and cyclodextrins. The substance having an inhibitory action on IGF-1 proteolysis may be any substance capable of blocking the hydrolysis reaction of IGF-1 in the body, and examples thereof include aprotinin, antipain, TPCK, PMSF, trypsin inhibitor, iodoacetate and Proteolytic enzyme inhibitors such as nafamostat, casein, casein hydrolyzate, soy protein, soy protein hydrolyzate, whey protein,
Examples thereof include proteins such as wheat proteins or partial degradation products thereof and proteolytic protectants such as cyclodextrins. In particular, a substance having both a surface active action and an IGF-1 degradation inhibiting action, such as casein and casein hydrolyzate, is preferable.

The amount of the substance having an inhibitory promoting action on IGF-1 and / or the substance having an inhibitory action on decomposition is not particularly limited, but preferably 0.1 to 100 times by weight of IGF-1. More preferably 0.5 to 10
It is 0 times.

The dose of the oral administration preparation of the present invention is
It depends on the patient's severity, drug tolerance, etc., but is usually about 1 to 5 as IGF-1 per adult per day.
000 mg protein, preferably about 10 to 1000 mg
It is about protein and can be administered once or in divided doses.

[0016]

【Example】

Experimental Example 1 (Experimental method) SD male rats (body weight 220 to 270)
g) was used. Rats fasted for 12 hours were intragastrically administered with a drug solution by an oral probe, and then fixed in a Ballman cage and subjected to cannulation of the femoral artery over time (15 minutes, 30 minutes, 1, 2, 3, 6). , 9 and 12 hours). The dose was human IGF-1, 1 mg / kg, and the administration liquid was human IGF-1, 1 mg / 5 ml physiological saline. Human IGF-1 in plasma was quantified by a conventional method by the RIA method using a monoclonal antibody.

(Results) The bioavailability (average of 4 cases) determined from AUC was 9.6%. Therefore, as a physiologically active peptide, absorption is very good.

Experimental Example 2 (Experimental Method) The experiment was carried out in the same manner as in Experimental Example 1 except that the drug solution to which the proteolytic enzyme inhibitor aprotinin was added at a concentration of 0.05 w / v% was used.

(Results) The bioavailability determined from AUC was 19.2%. Therefore, as a physiologically active peptide, absorption is very good.

Experimental Example 3 A drug solution containing casein at a concentration of 1 w / v% was used as a drug solution for administration, and ¹²⁵ I-IGF- was used instead of human IGF-1.
1 (see Japanese Patent Application Laid-Open No. 4-282399), and the quantification was performed in the same manner as in Experimental Example 1 except that it was determined by measuring the radiation dose of the TCA precipitate.

(Results) The bioavailability determined from AUC was 85.6% and the absorption was very good.

Example 1 Capsules or enteric-coated capsules were manufactured according to a conventional method using the drugs having the formulations shown in Table 1.

[0023]

[Table 1]

Example 2 With the formulation shown in Table 2, tablets are produced according to a conventional method.

[0025]

[Table 2]

[0026]

EFFECT OF THE INVENTION IGF- which is a medicinal substance in the present invention
1 is easily absorbed from the digestive tract by oral administration,
Since it has a medicinal effect, it can be easily treated with IGF-1 by preparing it as an orally administered preparation.

Claims (6)

[Claims] 1. An oral administration preparation containing insulin-like growth factor 1. 2. The oral administration preparation according to claim 1, which contains insulin-like growth factor 1 and a pharmaceutically acceptable additive. 3. Insulin-like growth factor 1, a substance having an absorption promoting action on insulin-like growth factor 1 and / or
The oral administration preparation according to claim 1 or 2, which further comprises a substance having an inhibitory effect on the degradation of insulin-like growth factor 1. 4. The orally-administered preparation according to claim 3, which contains insulin-like growth factor 1 and a substance having an inhibitory action on the degradation of insulin-like growth factor 1. 5. The orally-administered preparation according to claim 4, wherein the substance having an inhibitory effect on the degradation of insulin-like growth factor 1 is a proteolytic protectant. 6. The orally-administered preparation according to claim 5, wherein the proteolytic agent is casein.