JPS6360940A - Preventive or remedy for cataract - Google Patents

Abstract

PURPOSE:To provide a preventive or remedy for cataract, by using a parathyroid hormone as an active component. CONSTITUTION:A parathyroid hormone which is a hormone active to increase the serum calcium level and decrease the phosphorus level in living body is used as an active component of the objective agent. The parathyroid hormone is e.g. natural human-originated h-PTH(1-84), bovine-originated b-PTH(1-84), rat-originated r-PTH(1-84), synthetic h-PTH(1-38), h-PTH(1-34)NH2, [Nle<8>,<18>]h-PTH(1-34), etc. The remedy is administered as an injection, trans- rectal, transcutaneous or trans-nasal absorbing agent or eye drop at a dose of 0.1-800mug, preferably 2-300mug as h-PTH(1-34) in the case of intramuscular injection.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a composition for the prevention or treatment of cataracts containing parathyroid hormones as an active ingredient.

[Conventional technology]

A cataract is a condition in which the optical transparency of the crystalline lens is reduced due to changes in the matrix of the lens or the deposition of certain substances.
Known acquired cataracts in humans include senile cataracts and diabetic cataracts.

Cataracts are caused by abnormalities in substance metabolism within the eye's lens, resulting in denaturation and aggregation of the proteins that make up the lens, making it difficult for light to reach the retina.

In recent years, as the population ages, senile cataracts tend to increase. Although it is known that cataract surgery can improve vision, there have been many requests to rely on drug therapy due to fear of surgery. However, it is well known that drugs are not very effective against cataracts, and there has been a need for more effective drugs.

[Problem that the invention seeks to solve]

As mentioned above, as human lifespans increase and the population ages, the number of people suffering from senile cataracts and lens clouding that progress with age and for which there is no legally clear cause is increasing. It's coming. It is said that up to 90% of the population over the age of 75 suffers from geriatric curvature disorder, and it would be desirable for the majority of patients if this disease could be cured with drug therapy rather than surgery. Needless to say.

Cataracts occur due to the action of quinone on lens proteins, the oxidation of the structural proteins and lipid membranes of the lens, and the slowing down of the turnover of these proteins and lipids, resulting in the generation of denatured proteins and lipids, resulting in the loss of transparency of the lens. It is said to occur due to loss of sexuality. Ascorbic acid, reduced glutathione, and vitamin E, which are quinone inhibitors and antioxidants, are used to improve oxidation and turnover.
, cysteine, thiobronin or salivary gland hormones (
parotin) is used as a therapeutic drug.

However, the effects of such drugs are said to be unclear. On the other hand, in diabetic cataractopathy, when glucose in the aqueous humor increases, excess glucose also accumulates in the crystalline lens, which activates the sugar metabolic pathway (sorbitol pathway) that leads to fructose via sorbitol. . Then, aldose reductase, one of the enzymes in this system, works to produce sorbitol as a metabolite, but sorbitol is not metabolized and accumulates within the lens, increasing the osmotic pressure within the lens and allowing water to flow in. This causes the lens to swell and become cloudy, leading to cataracts.

On the other hand, attempts have been made to treat diabetic cataracts using aldose inhibitors, which suppress the production of aldose reductase, but this is said to be undesirable because it also inhibits the physiologically necessary aldose reductase. ing. [Ige et al., ed., Collection of Animal Model Use for New Drug Development (1985) R&D Planning, Tokyo] [Means for Solving Problems] The present inventors have been conducting research on calcium metabolism in living organisms for many years. He has continued to synthesize various types of parathyroid hormone IQ, which is one of the calcium metabolism regulating hormones, and has conducted research on its physiologically active action mechanism. The present invention was completed by discovering that the onset of the disease can be effectively suppressed.

That is, the present invention relates to a preventive or therapeutic agent for cataract containing parathyroid hormones as an active ingredient.

An object of the present invention is to provide a preventive or therapeutic agent for cataract containing parathyroid hormones as an active ingredient.

parathyroid hormone
one, PTH, barathyloid hormone] is a general term for hormones that exhibit serum calcium-raising effects and phosphorus-lowering effects in vivo. For example, depending on the animal species, human parathyroid hormone (h-pTH (1-84)), ,
tl, T, et al. Biochemistry, 17
, 5733 (1978)] bovine parathyroid hormone (
b-PTH(1-84) (J, T, Potts
Am, J. Med, 50.639 (197
1)), rat parathyroid hormone [γ-PYH (18
4) ) (1leinrich G, et al, J, B
oil.

Chem,, 259, (5), 3320 (19
B4)) C(1-84) indicates the number of amino acid residues] is classified as a polypeptide consisting of 84 amino acids of natural PTH(1-84).

Parathyroid hormone (PTH, h-PTH as needed)
, b-PTH, γ-PTH, etc.) is known to be reproduced by a peptide containing 34 amino acid residues on the N-terminal side of the peptide. [Biochemistry Dictionary, Tokyo Kagaku Dojin (1984)] In the present invention, these PTH fragments are also included in its purpose. The present invention also includes PTH fragments in which some of the amino acid residues in these heat input type PTH fragments are replaced with other amino acid residues.

In the present invention, these PTH fragments and PTH fragments in which amino acid residues are replaced with other amino acids are collectively referred to as parathyroid hormone derivatives (hereinafter sometimes referred to as PTH derivatives). And these PTH
The derivatives are collectively referred to as parathyroid hormones (PTH). The naming and description method for PTHfi is based on the International Union of Biochemistry (I).
UB) are described according to the nomenclature.

In addition to the above-mentioned cases, examples of PTH0 include h-PTH (
1-84) (JP 57-81448), h-PTH
(1-34) CG, W, Trc4ear et al.! l0
PPE-5eyler's Z, Physiol,
Chem, + 355.415 (1974)), h
PTH(134) NHz
052)(Nfe”34]h--PTH(1-34),
(Nj7 e””, Tyr”) h-PTH(1-
34) (JP-A-55-113753), (Nle”34
]h-PTH(134)NHZ (JP-A-6L-24
598), (N le ” 18% Tyr34]h
- PTH (134) NHz (JP-A-6O-34
996), γ-PTH(1-34)CKentmann
+ H, T, et al., Endocrinol, 1
17, (3), 1230 (1985)), (N 1
el++ 21, Tyr34] γ-PTH (1-34
), (NAe"z+)γ-PTH(1-34) (Patent Application 1986-207274), (Nl e"', Tyr34
]γ-PTH(1-34)NH2 (JP-A-6L-576
00), b-PT H(1-34) (Rosen
Blatt, M.

In Pathbiol, Ann, 11-153.
(1981), Rav-erPress, N.
Y, ), b-PTH(134) NH2, (N
Ae””]b-PTH(1-34), [N1 e
II ・I II, Tyr"] b-PTH (134)
CNle""]b PTH(134) NHz and (Nj2 e"", Tyrko4]b-PTH(1-3
4) NH2 (same as above), etc. can be mentioned.

In the present invention, all peptide hormones that exhibit serum calcium increasing effects and phosphorus decreasing effects in vivo are included as PTH4fi of the present invention. Also, P.T.
The present invention includes H [other than these examples, which are used for the purpose of the present invention.

Examples of the form of the drug in the present invention include injections, rectal absorption preparations, transdermal absorption preparations, nasal absorption preparations, and eye drops. These dosage forms are not limited in any way.

Injectable preparations are preferably used for intramuscular administration, rectal absorption preparations are generally used in the form of herbal medicines, and transdermal preparations are for nasal passages and other various transdermal absorption preparations. Eye drops are generally used in the form of eye drop formulations.

These drugs are formulated into suitable dosage forms of their respective conventional drug forms. Injections include, for example, h-PTH (1-3
Dissolve 4) in distilled water for injection containing an appropriate amount of buffering agent, tonicity agent, pH adjuster, and stabilizer, pass through a sterilization filter, sterilize the solution, and dispense the solution into ampoules. , or prepared by dissolving h-P T H (1-34) in distilled water together with a filler and a stabilizer, sterilizing it through a sterilizing filter, dispensing it into a vial, and freeze-drying it. be done. Rectal absorbents are, for example, h-PTH (1
-34) is dissolved or dispersed in distilled water or an oily vehicle using an absorption enhancer with chelating ability such as sodium pectate or sodium alginate, or a hypertonic agent such as sodium chloride or glucose as appropriate, and prepared as a suppository for rectal injection. or prepared as a suppository (UK Published Patent No. 2092)
(See specification No. 002 and specification No. 2095994).

Furthermore, a preservative such as henzalkonium chloride may be appropriately added to the above-mentioned sterilized product to prepare a preparation for nasal administration filled with sterile gas. When such drugs are intramuscularly injected, the single dose of h-PTH (1-34) is 0.1 to 800 μg, preferably 2 to 300 μg/dose.
times are administered. Other preparations and other parathyroid hormone derivatives may be administered according to the weight of h-pTH(1-34). In addition, the number of administrations may be 1 to 5 times per day.

〔Effect of the invention〕

The effect of h-PTH (1-34) on cataract was investigated under the following conditions.

Feeding rats with a diet high in galactose causes entropion (N, J, Unakar and
J.

Y, Jsui Experimental Eye
Re5arch, 36.685-694 (1983
), etc.] are known. Therefore, 24 3-week-old male Wistar rats were divided into 4 groups of 6 rats each. Group 1 served as a normal control group and was fed a normal diet. Group 2 served as a pathological control group that was fed a diet containing 50% galactose. Group 2 and Group 4 were groups in which h-PTH (1-34) was subcutaneously administered daily at 0.375 μg/kg and 6 μg/kg, respectively, from the start day of the experiment. The experimental period was 13 days, and observations were continued every day. Table 1 shows that the day when the nucleus of the crystalline lens becomes clearly opaque compared to the control is evaluated as the onset of cataract. significantly suppressed.

As is clear from the above results, administration of the drug of the present invention clearly suppressed the expression or onset of cataract, and therefore the drug of the present invention is useful as a preventive or therapeutic agent for cataract. Also, PTH used in the present invention
[ is an endogenous substance synthesized by the body itself or a derivative thereof, and has low toxicity.

Examples of the present invention are listed below, but the present invention is not limited thereto.

Example 1 60 mg of h-PTH (1-34) was added to mannitol log,
It was dissolved in 2β of distilled water for injection along with an appropriate amount of other stabilizing agents, and then passed through a sterilization filter, filled into 1 ml vial each, and lyophilized to obtain an injection containing 30 μg/vial of h-PTH(1-34).

Example 2 Distilled water for injection 6 in which 60 mg of h-PTH (1-34) was dissolved in appropriate amounts of a buffer, an isotonizing agent, a pH adjuster, and a stabilizer.
1, then passed through a sterilization filter, filled in 1 ampoule (1 ml), sealed and melted.
An intramuscular injection containing 10 μg/ampule of PTH(1-34) was obtained.

Example 3 h-PTHloljg, sodium alginate 50mg
, 50 mg of sodium chloride, appropriate amount of other stabilizers, and 1 m of distilled water.
1 to obtain a rectal injection.

Example 4 h-PTH 100 mg, sodium pectate 50 g,
50g of sodium chloride, appropriate amount of stabilizing agent and 100ml of distilled water
1 and Lytepsol H-1, which was heated and melted.
5 was uniformly dispersed to make 1 kg, and 1 g of each was filled into suppository containers to obtain rectal suppositories.

Example 5 Dimyristoylfuosatidylcholine (DMPC) 0.
15 mmol in chloroform:methanol (1:1)2
mg, and the solvent was distilled off so that it was adsorbed on the wall of the container in the form of a film. To this, h-PTH (1-34)4.
Dissolve 3 μmol in 750 mg of physiological saline for injection, add 4
It was heated to 0°C and shaken. After cooling to 10℃, return to 40℃
After heating at room temperature and passing through a sterilization filter, l ml
h-PTH (1-34
) 20 μg/ampule of intramuscular injection was obtained.

Example 6 0.15 mmol of DMP CO was dissolved in 2 mf of chloroform:methanol (1:1), and the solvent was distilled off so that it was adsorbed on the wall of a container in the form of a film. To this h-PT
4.3μmol of H(1-34) in 750mg of distilled water for injection
was added to the solution, heated to 40°C, and shaken. After cooling to 10℃, heating again to 40℃ and returning to room temperature, Mannitol 1
．． Add 8g of h-PTH (1-34), pass through a sterilization filter, fill 1ml each into vials, and freeze-dry.
An injection containing 20 μg/vial was obtained.

Claims (5)

[Claims] (1) Cataract treatment agent containing parathyroid hormones as an active ingredient. (2) The preventive or therapeutic agent for cataract according to claim 1, wherein the parathyroid hormone is a natural or synthetic parathyroid hormone. (3) Natural parathyroid hormones are h-PTH (1-8
4), b-PTH (1-84) or γ-PTH (1-
84) The preventive or therapeutic agent for cataract according to claim 2. (4) Synthetic parathyroid hormones are h-PTH (1-3
8), h-PTH (1-34), h-PTH (1-34
)NH_2, [Nle^8^,^1^8]h-PTH(
1-34), [Nle^8^,^1^8, Tyr^3^
4] h-PTH (1-34), [Nle^8^,^1^
8] h-PTH (1-34) NH_2, [Nle^8^
,^1^8, Tyr^3^4] h-PTH (1-34)
NH_2, γ-PTH (1-34), [Nle^8^,
^2^1] γ-PTH (1-34), [Nle^8^,
^2^1, Tyr^3^4] γ-PTH (1-34) [
Nle^8^,^2^1, Tyr^3^4] γ-PTH
(1-34)NH_2,b-PTH(1-34),b-
PTH(1-34)NH_2, [Nle^8^,^1^
8] b-PTH (1-34) [Nle^8^,^1^8
]b-PTH(1-34)NH_2, [Nle^8^,
^1^8, Tyr^3^4] b-PTH (1-34) or [Nle^8^, ^1^8, Tyr^3^4] b-
Claim 2 which is PTH(1-34)NH_2
A prophylactic or therapeutic agent for cataracts as described in Section 1. (5) The preventive or therapeutic agent for cataract according to claim 1, wherein the therapeutic agent is an injection, a rectal absorption agent, a transdermal absorption agent, a nasal absorption agent, or an eye drop.