JPH10101577A - Preventive and therapeutic medicine for motion range reduction disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine capable of efficiently using for prevention and/or treatment of a motion range reduction disease caused by arthrodesis and arthropathy by making the medicine contain insulin-like growth factor-I as an active ingredient. SOLUTION: This medicine contains insulin-like growth factor-I (preferably natural type human insulin-like growth factor-I) as an active ingredient Generally, this medicine is preferably administrated by intraarticular injection or successive administration and perfusion by means of drainage and the like to the articulation accompanied by the motion range reduction. At this time, this medicine may be administrated at a dosage of about 1μg-10mg/kg, preferably about 1-100μg/kg, a day as the amount of the active ingredient to an adult. By this process, this medicine is excellently useful as a medicine capable of making radical treatment possible.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicament useful for the prevention and / or treatment of decreased range of motion of joints.

[0002]

2. Description of the Related Art It is known that, when a joint is fixed for a long time with a cast or the like during treatment of a fracture or the like, the range of motion of the joint decreases after the fixation is released. Further, in a joint disease including osteoarthritis, pain is caused during walking as an initial symptom, so that the muscle strength gradually decreases and the range of motion of the joint may decrease. Such reduced joint range of motion is a symptom in which the joint cannot be sufficiently extended or bent (reduced motility in flexion and extension of the joint) or a symptom in which the joint cannot be rotated or twisted (flexibility in the rotation of the joint). ) And the like.

[0003] One of the mechanisms of such a decrease in the range of motion of the joint caused by joint fixation or joint disease is a decrease in the lubricating ability of synovial fluid, or a concomitant joint failure due to malnutrition in the joint. The occurrence of contraction is considered (Takashi Kikuchi et al .: Pharmacology and Treatment, 21, 401, 1993). In addition, it has been reported that when a joint is fixed for treatment of a fracture or a ligament injury that has occurred around a joint such as a knee or a shoulder, a mechanical property of the ligament parenchyma or the like changes with time (day setting). Journal, 69, S1395,
1995). However, there are many unclear points about the pathogenesis of hypomobility of the joint, and at present, little is known about the effects of joint fixation on ligaments, tendons, and muscles.

[0004] Anti-inflammatory agents, hyaluronic acid preparations, and the like are mainly used for the prevention and treatment of decreased range of motion of joints. However, anti-inflammatory agents are used for the purpose of removing pain associated with inflammation of the joint and its surroundings, and hyaluronic acid preparations are merely introduced into the joint membrane as a lubricant. It does not go beyond the scope of symptomatic treatment and does not reduce or eliminate the unhealthy state of ligaments, tendons, and muscles due to joint contracture or fixation, and cannot cure the disease.

On the other hand, insulin-like growth factor-I (hereinafter sometimes abbreviated as "IGF-I") is a single chain produced from liver (and kidney) depending on pituitary growth hormone. Polypeptide (for isolation of human IGF-I, see Rinderknecht, et al., Proc. Natl. Acad. Sci.,
USA, 73, 4379, and its amino acid sequence is described in J. Biol. Chem., 253, 2769, 1978 and FEBS.
Lett., 89, 283, 1978), has a sugar uptake action to cells, an amino acid uptake promotion action, a protein synthesis promotion action, a cell growth promotion action, a differentiation promotion action, etc., such as muscle and bone. It is known to act on many tissues and organs. IGF-I is also known to promote cartilage growth and matrix synthesis.

[0006] The application of IGF-I as a medicament is described as a therapeutic agent for dwarfism, a growth promoting agent for short stature (for basic research, Endocrinology, 124, 2519, 1989 and J. Endocrin).
ol., 112, 123, 1987), a therapeutic agent for Type A diabetes exhibiting insulin resistance (N. Engl. J.
Med., 317, 1987), a therapeutic agent for muscular dystrophy (Japanese Unexamined Patent Publication No.
In addition to the above, application as a therapeutic agent for ulcers, trauma and burns is being studied. However, there is no report on the effect of IGF-I on joint contracture or on the unhealthy state of ligaments, tendons, and muscles around joints caused by joint fixation.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a medicament useful for preventing and / or treating such reduced joint range of motion caused by joint fixation or joint disease. There has not been provided a drug capable of preventing and / or curatively treating hypomobility of the joint, and such a drug is expected to be extremely useful clinically.

[0008]

The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, when IGF-I is administered into a knee joint accompanied by a decrease in the range of motion of the joint, the motility of joint flexion is reduced. Was found to be significantly improved. The present inventors have confirmed the preventive and therapeutic effects of IGF-I on decreased range of motion of joints based on the above findings, and have completed the present invention.

That is, the present invention provides an insulin-like growth factor
Prevention of reduced range of motion of joints containing -I as an active ingredient
Or a therapeutic agent is provided. According to a preferred embodiment of the present invention, the insulin-like growth factor-I is natural human IGF-
The above-mentioned prophylactic and / or therapeutic agent which is I; the above-mentioned prophylactic and / or therapeutic agent in the form of a pharmaceutical composition comprising the active ingredient insulin-like growth factor-I and a pharmaceutical additive; knee osteoarthritis, chronic For the prevention and / or treatment of rheumatoid arthritis, osteoarthritis, cervico-shoulder-arm syndrome, shoulder periarthritis, diseases consisting of forty shoulders, fifty shoulders, and temporomandibular disorders, and / or reduced range of motion caused by Gibbs fixation The above-mentioned prophylactic and / or therapeutic agent to be used; the above-mentioned prophylactic and / or therapeutic agent for local administration into a joint with reduced joint range of motion; and the above-mentioned prophylactic and / or therapeutic agent in the form of an ampoule for injection or a lyophilized powder for injection.
Alternatively, a therapeutic agent is provided.

According to another aspect of the present invention, the use of an insulin-like growth factor-I for the manufacture of a medicament for preventing and / or treating the above-mentioned decreased range of motion of the joint, preferably the above-mentioned pharmaceutical composition, and A method for preventing and / or treating hypokinetic range of motion, comprising the step of administering to a mammal, including a human, an effective amount of insulin-like growth factor-I.

[0011]

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "insulin-like growth factor-I" refers to natural IGF-I derived from mammals such as human, monkey, horse, or sheep,
And a non-natural IGF-I having substantially the same biological activity as the natural IGF-I. Non-natural IG
As FI, for example, in addition to partial fragments of natural IGF-I, substitution, insertion, and / or deletion of one or more amino acid residues with respect to the amino acid sequence of natural IGF-I Variants to which modifications have been made can be given. In addition, non-natural IGF-I includes human, monkey, horse,
Or a fusion formed by binding partial fragments of natural IGF-I derived from two or more different species selected from mammals such as sheep; natural IGF-I derived from birds, amphoteric, reptile, or fish And derivatives containing the above-mentioned modifications to the amino acid sequences thereof.

For example, a tag having several amino acids deleted from the N-terminus or a tag comprising about 1 to 10 histidines at the N-terminus from the viewpoint of increasing the activity, increasing the stability, and / or purifying the peptide. It is also possible to add an array or the like.
In addition, insulin-like growth factor-I includes the above-mentioned natural type IGF-I
Alternatively, a polypeptide comprising an unnatural IGF-I to which any saccharide (monosaccharide, disaccharide, oligosaccharide, or polysaccharide) or lipid is bound, or a polypeptide in which the polypeptide is phosphorylated Included. In addition, insulin-like growth factor-I
In addition to the above substances in free form, hydrochloride, acetate,
Alternatively, an acid addition salt such as a paratoluenesulfonic acid salt, or a base addition salt such as an ammonium salt or an organic amine salt is included. The method for producing insulin-like growth factor-I is not particularly limited, and may be a method produced by a method not available to those skilled in the art, such as recombinant DNA technology, peptide synthesis, or cell culture. When the medicament of the present invention is applied to humans, it is preferable to use human-derived natural IGF-I.

Regarding human-derived natural IGF-I, J. B.
iol. Chem., 253, 2769, 1978 and FEBS Lett., 89, 28
3, 1978, the amino acid sequence of which is described in Proc. Natl. Acad. Sci., USA, 7
3, 4379, 1976. Regarding IGF-I by recombinant DNA technology, for example, see European Patent Publication No. 12
No. 3228, No. 128733, and No. 219814, and the production method by the peptide synthesis method is described in Proc.
Natl. Acad. Sci, USA, 80, 2216, 1983. Further, with respect to variants, EP-A-158892
No. 346429, JP-A-62-169733, JP-A-1-
No. 50899, No. 1-63597, No. 1-66198,
No. 1-66199, and Proc. Natl. Acad. Sc
i., USA, 83,4904, 1986; Biochem. Biophys. Res. Com.
mun., 149, 398, 1987; Biochem. Biophys. Res.
n., 149, 672, 1987; Endocrinology, 123, 373, 1988;
J. Biol. Chem., 263, 6233, 1988; and Biochem. Bi.
ophys. Res. Commun., 165, 766, 1989.

Accordingly, natural IGF-I or non-natural IGF-I
It will be readily appreciated that those skilled in the art can readily obtain the following according to the methods described in these publications or by making appropriate alterations and modifications thereto. Whether or not non-natural IGF-I has substantially the same biological activity as natural IGF-I can also be easily determined according to the methods described in these publications. In this specification, the term “non-natural IGF-I
In the case of "having substantially the same biological activity as IGF-I", the non-natural IGF-I has some or all of the biological activity of the natural IGF-I, It means that it has a preventive and / or therapeutic effect of natural IGF-I on reduction of the spectrum. However, non-natural IG
The biological activity of FI need not be substantially the same as that of natural IGF-I.

As the medicament of the present invention, the above-mentioned insulin-like growth factor-I can be used as it is. Generally, one or more of the above-mentioned insulin-like growth factor-I and an additive for pharmaceutical preparation are used. It is preferred to prepare a pharmaceutical composition comprising and administer it to the patient. The medicament of the present invention is intravenously injected,
Parenteral systemic administration, such as infusion or intrarectal administration, may be used, or local administration, such as local injection or transdermal administration, to a joint with a reduced range of motion. From the viewpoint of therapeutic and / or prophylactic effects, local administration, particularly local injection into joints, is preferred. As a pharmaceutical composition suitable for such a dosage form, for example, the above-mentioned insulin-like growth factor-I and an appropriate pharmaceutical additive, distilled water for injection, physiological saline, an aqueous medium such as an aqueous glucose solution, glycerin Injectables in the form of a solution dissolved in a non-aqueous medium such as, or a mixture thereof are suitable. Such injections are generally provided as ampules for injection or lyophilized powders for injection (filled vials).

The method for producing the pharmaceutical additive and the pharmaceutical composition is not particularly limited, and any pharmaceutical additive and production method available in the art may be used. Pharmaceutical additives include, for example, buffers such as phosphate, borate and citrate; pH adjusters such as sodium hydroxide, hydrochloric acid and acetic acid;
Isotonic agents such as glucose and sodium chloride; preservatives such as benzyl alcohol, benzalkonium chloride and phenol; soothing agents such as procaine hydrochloride and lidocaine hydrochloride; solubilizing agents such as sodium salicylate and mannitol; A stabilizer or the like can be used. In addition, in the preparation of the lyophilized powder, in addition to the above-mentioned additives for formulation, carboxymethylcellulose,
Excipients such as sodium alginate may be used. However, pharmaceutical additives are not limited to these,
It goes without saying that appropriate ones can be used depending on the type of the pharmaceutical composition and the preparation method.

Further, as other topically administrable pharmaceutical compositions, needle-like pellets containing an effective amount of IGF-I,
Examples include microcapsules, nanocapsules, nanospheres, liposomes, lipid microspheres, and gelled preparations. Various types of these pharmaceutical compositions are known, and any of them may be used. Alternatively, a pharmaceutical composition produced by appropriately combining these formulation techniques may be used. These pharmaceutical compositions are preferred from the viewpoints of long-lasting drug efficacy and reduction of the number of times of administration, but the base used as a pharmaceutical additive is biocompatible, biodegradable, and biosoluble. Desirably. Furthermore, one or more drugs such as steroidal or non-steroidal anti-inflammatory drugs, hyaluronic acid preparations, synthetic antibacterial agents, and antibiotics can be added to the medicament of the present invention.

The medicament of the present invention can be used for the prevention or treatment of reduced range of motion of joints. As used herein, the term "hypotenosis of joint derangement" means that at least the kinematics of extension or flexion of a joint is substantially reduced as compared with that of a healthy person (low motility in flexion and extension of joints). And / or a disease in which the flexibility of rotation or torsion of a joint is substantially reduced as compared with that of a healthy person (flexibility in joint torsion). Although the medicament of the present invention can be applied to a disease characterized by the above-mentioned pathological condition, the judgment of the suitability of the disease should not be limited solely to the expression “reduced range of motion of the joint”. It goes without saying that a skilled physician can easily determine whether or not a symptom presented by a patient matches the above-mentioned condition or whether or not the disease can be applied to the medicament of the present invention.

Examples of the disease in which the range of motion is decreased include, for example, knee osteoarthritis, rheumatoid arthritis,
Osteoarthritis, neck and shoulder arm syndrome, periarthritis of the shoulder, forty shoulders, fifty shoulders, temporomandibular disorders can be mentioned. In addition, the range of motionless joint is sometimes caused by a temporary or long-term joint fixation such as a fracture or a cast fixation accompanying surgical treatment.

[0020] The administration of the medicament of the present invention is generally performed by intra-articular injection of a predetermined amount of a single dose or a plurality of doses into a joint accompanied by a decrease in the range of motion of the joint. It is performed by continuous administration or perfusion through the When the medicament of the present invention is administered once or more than once, usually about 1 μg to 10 mg / kg, preferably about 1 to 100 μg / day as an active ingredient per adult per day.
The dose may be in the range of kg. The number of times of administration is not particularly limited, but is preferably usually 1 to 2 times / week. However,
The dosage and the number of administrations are not limited to those described above, and it is possible to appropriately increase or decrease the dosage according to the purpose of treatment or prevention, the symptoms presented by the patient, the patient's age, body weight, concomitant medications, etc. Needless to say.

[0021]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples. Example 1 (Example of formulation) 0.6 g of sodium chloride, 0.6 g of sodium acetate and 0.9 g of benzyl alcohol were added to and dissolved in about 70 ml of water for injection, and recombinant human IGF-I (rhIGF-I, Genentech) was added.
1.0 g was added and dissolved. PH this solution with 0.1 N acetic acid
Adjust to 5-6, then add distilled water for injection to bring the total volume to 10
The volume was 0 ml. This solution was aseptically dispensed into 1 ml ampules using a membrane filter to prepare an injection containing rhIGF-I (10 mg / ml).

Example 2 (1) Preparation of an animal model of hypomobility of the joint 28 male Kbl: NZW (SPF) rabbits (Kitayama Labels), 12 weeks old, housed in individual cages were used. After anesthetizing the rabbit with ketamine hydrochloride and xylazine hydrochloride and shaving the right hind limb,
It was wrapped with a stocking net and cast pad from the upper thigh to the apex. Thereafter, the knee joint was fixed in the extended position using casting tape for 3 weeks. During that time, the cast was rewound once a week, the cast was cut out so that the administration site could be confirmed for administration other than on the day of the rewind, and after administration, the cast was adhered and reinforced with surgical tape to continue fixing. The range of motion of the joint was measured once a week during the fixed period and twice a week after the release of the fixation, and the range of motion of the right knee joint was measured as follows. The animal's knee position was fixed under anesthesia, the distal part of the tibia was pulled vertically with a load of about 400 g, and the knee joint extension and flexion angles were measured.The difference was calculated as the range of motion. .

(2) Administration of IGF-I IGF-I (0.1 mg / kg) administration group, IGF-I (0.02 mg / kg) administration group,
And a physiological saline solution (Otsuka Pharmaceutical) administration group, which was an experimental group, and each administration specimen was administered into the right knee joint from the fixation start date to 3 weeks after release. Dosage and dosing interval should be 0.
1 ml / kg was administered twice a week at 3 or 4 day intervals, and the administration period was 6 weeks (total of 12 administrations).

(3) Test Results The measurement results of the range of motion of the joint are shown in FIG. As is evident from the results in FIG. 1, the joint excursions during the fixation period and after the fixation were significantly higher than those in the saline administration group in a dose-dependent manner in all IGF-I administration groups. Thus, the preventive and therapeutic effects of IGF-I on the reduction of the range of motion of the joint were confirmed. In addition, when the difference in the range of motion of the joint from the fixation release date was calculated and compared as the therapeutic effect, it is clear from the results in Table 1 that the difference in the range of motion of the joint from the date of fixation release in all IGF-I administration groups was The dose-dependently significant value was higher than that of the saline administration group, confirming a clear therapeutic effect of IGF-I administration on the decrease in the range of motion of joints (the values in the table indicate the angles of range of motion of joints). Is shown).

[0025]

[Table 1]

[0026]

EFFECT OF THE INVENTION The medicament of the present invention is effective for the prevention and / or treatment of decreased range of motion due to joint fixation or joint disease, for which no medicament capable of radical treatment has been provided. It has high utility as a medicine.

[Brief description of the drawings]

FIG. 1 is a diagram showing the preventive and therapeutic effects of the medicament of the present invention on hypomobility of the joint. In the figure, * indicates a 5% risk factor, and ** indicates a statistical significance with respect to a physiological saline administration group at a 1% risk factor.

Claims (6)

[Claims] 1. A preventive and / or therapeutic agent for hypomobility of the joint, which comprises insulin-like growth factor-I as an active ingredient. 2. Insulin-like growth factor-I is a natural human IG
The prophylactic and / or therapeutic agent according to claim 1, which is FI. 3. The prophylactic and / or therapeutic agent according to claim 1 or 2, which is in the form of a pharmaceutical composition comprising insulin-like growth factor-I and a pharmaceutical additive. 4. A disease comprising knee osteoarthritis, rheumatoid arthritis, osteoarthritis, cervico-brachial syndrome, periarthritis of the shoulder, forty shoulders, fifty shoulders, and temporomandibular arthrosis, and / or Gibbs fixation. The prophylactic and / or therapeutic agent according to any one of claims 1 to 3, which is used for prevention and / or treatment of reduced range of motion of the joint. 5. The prophylactic and / or therapeutic agent according to any one of claims 1 to 4, for local administration into a joint accompanied by a decrease in the range of motion of the joint. 6. The prophylactic and / or therapeutic agent according to claim 5, which is in the form of an ampoule for injection or a lyophilized powder for injection.