JPS63267716A - Remedy for urea cycle dysbolism - Google Patents

Abstract

PURPOSE:To obtain a remedy for urea cycle dysbolism, especially ornithine transcarbamylase deficiency, containing carnitine, acylcarnitine, etc., as an active ingredient and having low toxicity and excellent stability and preferably used by oral administration. CONSTITUTION:A remedy for urea cycle dysbolism obtained by containing at least one selected from carnitine, acylcarnitine and derivatives and salts thereof as an active ingredient. In addition to the above-mentioned compounds, carnitine chloride, carnitine phosphate, palmitoylcarnitine chloride, acetylcarnitine chloride, propionylcarnitine chloride, etc., are cited as the compound which is the active ingredient; however, L-carnitine and L-carnitine chloride are especially preferred. In use, the compound is converted into the form of pharmaceutical according to methods for administration using a normal pharmaceutical carrier together with the active ingredient. The method for oral administration is especially preferred.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to ornithine transcarbamylase (Ornithine transcarbamylase)
itine transcarbamylase, O
The present invention relates to a therapeutic agent for urea cycle metabolic disorders represented by T C) deficiency.

BACKGROUND OF THE INVENTION OTC deficiency is the most common disease among urea cycle metabolic disorders, and is known to exhibit Rey'-like syndromes such as hyperammonemia, vomiting, and impaired consciousness during attacks. To date, the treatment of chickenpox has been to limit the patient's protein intake to about 1.0 to 1.5 g/kg/day, and to use sodium benzoate to conjugate nitrogenous waste products with glycine and excrete them as hippuric acid. has been used with some success. In addition, secondary carnitine deficiency is observed in Reye and Reye-like syndromes, and it has been reported that this promotes mitochondrial dysfunction and is also involved in the progression of the disease.
Elucidation of the pathology of TC deficiency and development of drugs for its treatment are still not sufficient.

On the other hand, carnitine was discovered in 1905 by Dalevish (G
ulavitsch), Grimvelb (Krimb)
It is a compound first discovered from meat extracts by E. erg and Kutscher. 194
In 1977, Fracnkcl and Blewett discovered that unknown substances (named vitamins B and J) contained in yeast or liver extracts were essential for the growth of the brown rice beetle. In 1952, Carter (Car
ter) isolated the above-mentioned crystals having vitamin BT activity and confirmed that this was the same substance as carnitine.

Furthermore, carnitine is currently distributed in a wide range of organisms, from humans to microorganisms, and is known to be contained in large amounts in muscle and pancreatic juice. There is a series of research reports by Fritz et al.

I, B. et al., J. Lipid.
Res,,4. 279 (1963)).

Carnitine [(C113) 3 N C112Cl1(
C112COO] has the activity of promoting the uptake of Aeyl-Co A, an active fatty acid, into the mitochondria in β-oxidation of fatty acids in the mitochondria present in living cells. That is, carnitine converts Acyl-CoA into A(J'1-CoA through the action of carnitine transferase).
Instead of carnitine, it is said to quickly pass through the barrier, participate in β-oxidation in the endomembrane system, and help produce energy. Therefore, carnitine can be expected to have various pharmacological effects by utilizing its physiological effects, and various experiments have shown that carnitine mainly has effects such as increasing digestive motility, increasing secretion of digestive juices, and promoting growth. has been confirmed and has been shown to be effective in treating lipid metabolic diseases and muscular dystrophy diseases.

Problems to be Solved by the Invention The present inventors have been conducting extensive research with the aim of providing a drug effective for the treatment of urea cycle metabolic disorders represented by OTC deficiency. In the process, the above-mentioned carnitine, acylcarnitine, derivatives and salts, etc., have been used in various cases where it is known that the application of each compound is effective, although there is no example in which these compounds have been applied in the past. Surprisingly, we have discovered a new fact that when applied to patients with urea cycle metabolic disorder, which is not related to any disease, it can have excellent therapeutic effects.

□The present invention has been completed based on the above findings.

Means for Solving the Problems According to the present invention, there is provided a therapeutic agent for urea cycle metabolic disorder characterized by containing as an active ingredient at least one selected from carnitine, acylcarnitine, and their derivatives and salts. provided.

Compounds used as active ingredients of the therapeutic agent of the present invention include carnitine, acylcarnitine, carnitine chloride, phosphorylated carnitine, balmitoylcarnitine chloride, acetylcarnitine chloride, propionylcarnitine chloride, etc. , D-integrated or DL-integrated. Examples of the above-mentioned active ingredient compounds that can exhibit particularly excellent therapeutic effects include carnitine, particularly L-carnitine and L-lunitine chloride. Compared to other carnitine derivatives, it has low toxicity and excellent safety, and has the characteristics that virtually no side effects are observed when administered. It is effective as an active ingredient compound in a therapeutic agent for urea cycle metabolic disorders, particularly in a therapeutic agent for OTC deficiency.

Table 1 below shows the acute toxicity (L
D5o value), Litchfield and Wilcoxon (L 1tchfield and Wilcoxon)
) The results obtained according to the method are shown below.

Table 1 From Table 1 above, all of the tested carnitine and its derivatives have low toxicity, and L-carnitine in particular has very low toxicity in both rats and mice by any administration route. It is clear that it has low toxicity and is particularly suitable as an active ingredient compound for the therapeutic agent of the present invention.

The therapeutic agent for urea cycle metabolic disorders of the present invention is usually formulated into a pharmaceutical composition depending on the method of administration, using a general pharmaceutical carrier together with the above-mentioned compound as its active ingredient.

The above pharmaceutical composition can be prepared in a conventional manner using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. can. There are no particular restrictions on the administration method; oral administration,
Administration can be carried out by various routes such as intravenous administration, subcutaneous administration, and intraperitoneal administration, among which oral administration is particularly preferred. Examples of the formulation suitable for oral administration include tablets, gunpowders, powders, liquids (drinks), suspensions, emulsions, granules, and capsules. In the above, when forming into solid forms such as tablets and gunpowder, carriers such as lactose, sucrose,
Excipients such as sodium chloride, glucose, urea, starch, cocoa butter, hydrogenated vegetable fat, calcium carbonate, kaolin, crystalline cellulose, silicic acid, talc; water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac,
Binders such as methylcellulose, potassium phosphate, polyvinylpyrrolidone, gum arabic, tragacanth powder, gelatin; dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Sodium, stearic acid monoglyceride,
Disintegrants such as starch and lactose; disintegration inhibitors such as white sugar, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; starch and lactose Adsorbents such as , kaolin, bentonite, and colloidal silicic acid; lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Furthermore, tablets may be coated with conventional coatings as necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-coated tablets,
It can be a multi-layer tablet or the like.

The therapeutic agent of the present invention can also be in the form of a preparation suitable for intravenous administration, for example, an injection form such as an aqueous solution, emulsion, or suspension. When prepared as an injectable solution,
Emulsions and suspensions are preferably sterile and isotonic with blood, and when formed into these forms, diluents such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated Stearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In this case, the preparation may contain a sufficient amount of salt, glucose, or glycerin to adjust the isotonic solution.
Further, usual solubilizing agents, buffering agents, soothing agents, etc. may be added. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceuticals may be included in the therapeutic agent of the present invention, if necessary.

The amount of the active ingredient compound to be contained in the therapeutic agent of the present invention formulated into a dosage unit form is not particularly limited and can be appropriately selected within a wide range, but is usually 20 to 90% by weight in the total composition.
It is preferable to set the amount as contained. In addition, the dosage of the therapeutic agent of the present invention depends on various conditions, such as patient's age, sex, weight,
Although it is determined as appropriate depending on other conditions, severity of disease, administration method, etc., in the case of oral administration, the amount of the active ingredient compound is usually 5 to 2000 mg, preferably about 5 mg.
A pharmaceutical composition containing 500[IIg] may be administered, and the number of administrations may be increased or decreased as appropriate depending on the severity of the patient, with the standard of administration being 3 times a day.

EXAMPLES Below, Examples for the preparation of various formulation forms of the therapeutic agent for urea cycle metabolic disorders of the present invention are given, but the therapeutic agent of the present invention is not limited to these forms.

Example I L-lunithine 85 parts by weight Low-substituted hydroxypropylcellulose 11 parts by weight Light silicic anhydride 3 parts by weight Magnesium stearate 0.5 parts by weight Talc 0
．． 5 parts by weight Total 100 parts by weight Each of the above ingredients except magnesium stearate and talc were prepared as prescribed and added to 40 mQ (for 200 g of the final mixture) of 95% ethanol (or isopropyl alcohol added thereto). and practice well. Pass the mixture through a basket screen (diameter 0.5 to 1.0
1 to 50℃ at about 50℃.
After drying for 2 hours, the particles are sized using a #12-24 (mesh) sieve.

Next, magnesium stearate and talc are added and mixed according to the above recipe. Compress the mixture into tablets,
A therapeutic agent of the present invention in tablet form is obtained.

Example 2 Crystalline cellulose 25 parts by weight Carboxymethylcellulose 25 parts by weight Light silicic anhydride
5 parts by weight Macrogol 6000
20 to 5 parts by weight of L-lunithine to an additive consisting of 5 parts by weight.
The therapeutic agent of the present invention in the form of granules, fine particles, or powder is produced by containing 50 parts by weight.

Example 3 Crystalline cellulose 10 parts by weight Magnesium stearate 0.4 parts by weight Talc
The therapeutic agent of the present invention in the form of capsules is prepared by adding 20 to 50 parts by weight of L-lunithine Sh' to 0.8 parts by weight of the additive.

Example 4 Low-substituted hydroxypropylcellulose 6 parts by weight Light silicic anhydride 3 parts by weight Crystalline cellulose
5 parts by weight Magnesium stearate 0
．． 85 parts by weight of L-carnitine was added to an additive consisting of 5 parts by weight of 0.5 parts by weight of talc.
% Tablets (uncoated tablets, film-coated tablets,
The therapeutic agent of the present invention is produced in the form of sugar-coated tablets.

Example 5 Citric acid 2a+g/Deglucose 1.00 mg/mQ
200 to 500 m of L-lunithine to the additive consisting of
g/mQ, add sufficient amount of sterile purified water,
The therapeutic agent of the present invention is obtained in the form of an oral liquid in an ampoule, a glass bottle, or a synthetic resin container of 0 to 100 mm.

Example 6 200% L-lunithine was added to physiological saline or Ringer's solution.
~500 mg/or more, to obtain the therapeutic agent of the present invention in the form of an injection in an ampoule, vial, or plastic container for infusion of 10 to 500 mQ.

Examples of clinical trials conducted on the active ingredient compounds of the therapeutic agent of the present invention are listed below.

Clinical trial example 1 [Case 1] This case developed symptoms due to vomiting at the age of 8 months old, and as a result of liver OTC activity measurement using a liver biopsy at the age of 1 year and 9 months old, the liver OTC activity was 9.0 μmol/m
The female child was diagnosed with OTC deficiency due to her g protein level (22.5% of control), which was confirmed to be a mutant enzyme. This case was treated with an intake of protein (including essential amino acid preparations and protein-free milk) of 0.8 to 1.
Hyperammonemia was controlled by restricting the patient to 3 g/kg/day and continuing administration of sodium benzoate at 220 mg/kg/dad.

For the above case, as shown in Figure 1, at the first treatment (2 years and 2 months old), L-carnitine was administered at 50o+g/kg/da).
Administer L-L for 2 weeks, and at the second time (at 2 years and 10 months, after the attack, intermittently only when feeling cold or unwell), administer L-L-runitin at 100 mg/kg/day for 1 month. 17. For the third time, L-carnitine 100 tag/kg/day was continuously administered for 9 months starting from the onset of the attack at the age of 4 years and 3 months.

[Case 2] Vomiting attacks began around the age of 5, and the level of consciousness began to decline around the age of 6. At the age of 7 years and 11 months, high ammoniaemia was noticed due to the administration of palproic acid for suspicion of evilepsy. This case was a girl who was diagnosed with partial OTC deficiency after detailed examination including liver biopsy. In this case, the protein intake was 1.0 to 1. 5 g/kg/day,
The patient is being treated with oral administration of sodium benzoate at 250 mg/kg/day and arginine at 100 mg/kg/day.

In this case, since the age of 8 years and 11 months, L-carnitine 50
Administration of mg/kg/day has been started and has been continued for 6 months.

In each of the above cases, there was no change in treatment before and after carnitine administration.

<Test Results> The results of measuring serum carnitine levels and blood ammonia levels before and after carnitine administration in each of the above cases are shown in Table 2 below. Note that blood ammonia levels were measured by an enzymatic method. Table 2 also lists the equivalent values for the control.

Table 2 #1...p<Q, 005, #2...p<0.01,
#3...p<0.02 From Table 2 above, it can be seen that after carnitine administration, serum free carnitine values significantly increased and normalized in all cases. Acylcarnitine also increased, but no significant change was observed in the acyl/free ratio.

Furthermore, after carnitine administration, blood ammonia levels in both cases showed a significant decreasing trend.

Furthermore, Fig. 1 shows the changes in carnitine administration, attack frequency, blood ammonia, and serum free carnitine in Case 1.

In Figure 1, the upper row shows fluctuations in free carnitine values (shaded bands indicate normal values), the lower row shows fluctuations in blood ammonia levels, and the horizontal axis shows the test period (year).

This patient is prone to upper respiratory tract infections during the winter, and has had hyperammonemic attacks once or twice a month. Although treatment was required, only one attack was observed after carnitine administration, as shown in Figure 1.
Although the blood ammonia level at this time was 400 μg/dQ, the symptoms were mild (only vomited several times) compared to usual attacks, and the ammonia level improved quickly. In addition, I have not had any seizures in recent months, and my protein intake has been reduced to 1.
Although the dose may increase to 1.5 g/kg per day, seizures have not been induced.

Furthermore, as shown in Figure 1, this case had persistently low free carnitinemia, and normalization of free carnitine levels was observed only during carnitine administration.

On the other hand, in Case 2, the frequency of attacks has been gradually increasing, with a total of 5 hyperammonemic attacks in the last 10 months (blood ammonia = 140-268 μg/dR).
The patient's symptoms were relieved by several days of symptomatic treatment such as intravenous drip therapy, but to date no seizures have been observed since the administration of carnitine.

Regarding the above two cases, no characteristic changes were observed in the blood amino acids before and during the administration of L-lunitine, and no significant changes were observed in the amount of urinary orotic acid excreted.

[Brief explanation of the drawing]

FIG. 1 is a graph obtained by orally examining changes in serum free carnitine levels and blood ammonia levels in patients to whom the active ingredient compound of the therapeutic agent of the present invention was administered. (that's all)

Claims (2)

[Claims] (1) A therapeutic agent for urea cycle metabolic disorder characterized by containing as an active ingredient at least one selected from carnitine, acylcarnitine, and their derivatives and salts. (2) The therapeutic agent according to claim 1 for the treatment of ornithine transcarbamylase deficiency.