WO1999053941A1

WO1999053941A1 - Oral preparations containing trh derivatives

Info

Publication number: WO1999053941A1
Application number: PCT/JP1999/002006
Authority: WO
Inventors: Katsuji Sugita; Norihito Satoh; Takanori Yoshikawa
Original assignee: Shionogi & Co., Ltd.
Priority date: 1998-04-15
Filing date: 1999-04-15
Publication date: 1999-10-28

Abstract

Preparations for the oral administration of TRH derivatives characterized by containing the TRH derivatives, medium-chain triglycerides and, if desired, lecithin. Use of these preparations makes it possible to improve the oral absorbability of the TRH derivatives thereby elevating the bioavailability thereof.

Description

Specification

Oral formulation containing T RH derivative

The present invention relates to an oral administration preparation containing thyrotropin releasing hormone (hereinafter, abbreviated as “TRH”) or a derivative thereof. Background art

TRH is a discovered hormone from the hypothalamus, the structure, L one Piroguruta mill one L one Hisuchijiru L- Purorin'ami de - a (p- G lu- H is P ro- NH 2). It is known that T RH exerts various pharmacological effects by acting on the central nervous system as well as promoting the release of thyroid stimulating hormone and prolactin in the pituitary gland (Medical Topics Series, Neurobeptide'9). 1, Medical Review). TRH derivatives that have enhanced effects on the central nervous system also generally consist of three amino acids or their derivatives, similar to TRH, and most of them have a molecular weight of about 370-430. And described in, for example, the following literature [J. Med. Chem, 33, 2130-2137 (1990) and Japanese Patent Application Laid-Open No. 61-33197 (eg, talcirrelin; TA— 0910); Biomedical Research 14 (5) 317-328 (1993) and ZA7505965 (example: montilelin; CG3703); Arzneim.-Forsch / Drug Res., 39 , 297-303 (1989) and JP-A-56-83354 (Example: Posatirelin; RGH2202); Eur. J. Pharmacol. 276, 177-182 (1995); — 2 3 6 3 9 7 (Example: JTP— 2 9 4 2); Tokuhei 2—3 6 5 7 4 (Example: 1—Methyl L-1 4,5 Dihydrorotyl L—Histidyl L—Prolinami 5)-1 1 4 6 5 (Example: 2, 3, 4, 5 Tetrahi Draw 2 —Oxo—L-1 5 —Francarboryl L—Histidyl—L—Prolinamide; Tokuhei 3—2 3 6 3 9 7 (Example: (1S, 2R) —2—Methyl-4 Exo J. Pharmacol., 271, oxocyclopentylcarbonyl L-histidyl-L-prolinamide; 357 (1994) (Example: TRH-SR); JP-A-52-3080; Eur. J. Pharmacol. 277, 63-69 (1995) and JP-A-60-27982 (Example) Azetirelin; YM1463 3); JP-A-60-23233 (Example: DN1417): JP-A-62-234029; JP-A-56-8 No. 354; W096 No. 11 209; WO 98/088867, etc.].

By the way, these TRHs or derivatives thereof (hereinafter collectively referred to simply as TRH derivatives) are generally stable to enzymes in the gastrointestinal tract, but are absorbed from the gastrointestinal tract because of their high water solubility. Poor sex. In fact, for example, Tartirelin (T

A-0910) has been reported to have a low bioavailability of 3.9% after oral administration to rats (pharmacokinetics 12 (5) 460-474 (1997)). Therefore, most TRH derivatives have to be developed or used as injections, not as oral preparations. TRH has also been approved for the treatment of ataxia in spinocerebellar degeneration, for example, but due to oral absorption problems, patients with this disease need to be visited daily for treatment by injection. However, for patients with spinocerebellar degeneration with gait disturbance as the main symptom, daily medications at hospital visits pose difficulties in social life, and development of oral preparations is desired from clinical practice.

Under such circumstances, as an oral preparation of a TRH derivative, for example, a preparation containing polycarboxylic acid or oxycarboxylic acid (Japanese Patent Application Laid-Open No. 60-233226) has been reported. There is a demand for the development of oral preparations.

On the other hand, Japanese Unexamined Patent Publication (Kokai) No. 1-257715 discloses that esters and amides which are easily decomposable for enzymes in the digestive tract are dissolved or suspended in medium-chain fatty acid triglycerides. Oral preparations with reduced enzymatic degradation are described. Japanese Patent Application Laid-Open No. Hei 8-92288 discloses that a dihydrochenopyridine derivative, which is a poorly water-soluble drug, is mixed with a medium-chain fatty acid triglyceride and lecithin to improve the solubility and absorbability. Oral preparations with improved properties are described. Furthermore, WO 88/78771 describes a pharmaceutical composition containing lecithin and adapted for transdermal or transmucosal administration. However, there is no specific description in these documents about a method for improving the oral absorbability of a TRH derivative. In general, the oral absorption of drugs depends on their solubility in water and enzymes in the gastrointestinal tract. Various physical properties such as stability are involved, and even a person skilled in the art can improve the oral absorption of a specific drug only after intensive examination in view of the individual physical properties. There is no suggestion of improvement in oral absorption of the substance from the above-mentioned literature. Disclosure of the invention

The present inventors have conducted various studies on a method for improving the oral absorbability of a TRH derivative, and as a result, have found that a combination use with a medium-chain fatty acid triglyceride is very preferable. Furthermore, they found that oral administration of a combination of lecithin and triglyceride of medium-chain fatty acid improved oral absorption of TRH derivatives, and thus completed the present invention described below.

(1) An orally-administered preparation containing L-pyroglucyl-yl-L-histidyl-L-proline amide or a derivative thereof and a medium-chain triglyceride as a main drug.

(2) The preparation according to the above (1), further containing lecithin.

(3) The preparation according to the above (2), wherein the lecithin is soy lecithin.

(4) The preparation according to the above (1), wherein the preparation contains a medium-chain fatty acid triglyceride in an amount of 1 to 200 times (weight ratio) the main drug.

(5) The preparation according to the above (2), which contains lecithin in an amount of 0.1 to 10 times (by weight) the main drug.

(6) The active ingredient is the formula:

(In the formula, H et ¹ and H et ² each represent any of the following groups.

(R ¹ is hydrogen or alkyl; X is CH ₂ or 〇);

Z is CH ₂ or S;

R ² is alkyl, one CH ₂ OR ³ , one C〇NHR ⁴ , one COOR ⁵ or —CN (R ³ , R ⁴ and R ⁵ are each independently hydrogen, optionally substituted alkyl or substituted Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

(7) The rate of increase in body temperature after oral administration to reserpine-pretreated mice is about twice or more as compared with a preparation containing no medium-chain fatty acid triglyceride and lecithin, as described in (1) to (6) above. The preparation according to any one of the above.

(8) As described in any of (1) to (6) above, the bioavailability in a rat is about 30 times or more as compared with a preparation containing no medium-chain fatty acid triglyceride and lecithin. Preparations. Examples of the TRH derivative which is the main drug of the present preparation include various TRH derivatives described in the above-mentioned literatures, including the compound (I) represented by the formula (I). In the compound (I), alkyl in R ¹ and R ² independently includes straight-chain or branched alkyl having 1 to 10 carbon atoms, and includes methyl, ethyl, n-propyl, and isopropyl. , N-butyl, t-butyl, pentyl, hexyl, octyl, nonanyl, decanyl and the like, and preferably alkyl having 1 to 5 carbon atoms. And more preferably methyl.

Alkyl at R ³ , R ⁴ and R ⁵ includes linear or branched alkyl having 1 to 16 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl Hexyl, octyl, nonanyl, decanyl, pendenyl, dodecanyl, tridecanyl, tetradecanyl, pentadecanyl, hexadenicil, etc. Is methyl, ethyl, propyl and the like. The alkyl may be substituted by a substituent such as halogen (eg, F, C1, Br, I), hydroxy, amino, carboxyl, nitro and the like.

The aralkyl in R ³ , R ⁴ and R ⁵ (eg, benzyl, phenethyl and the like) may be substituted by the same substituents as in the above alkyl.

These may form pharmaceutically acceptable salts, such as acid addition salts (eg, tartaric acid, oxalic acid, fumaric acid, cunic acid, lingoic acid, lactic acid, oleic acid, palmitic acid, acetic acid, Hydrochloric acid, sulfuric acid, etc.).

The content of the TRH derivative in the present preparation is usually about 0.1 to 20% by weight, preferably about 0.5 to 20% by weight, more preferably about 1 to 10% by weight, based on the whole preparation.

The medium chain fatty acid triglyceride preferably has 8 to 12 carbon atoms in each fatty acid, such as ODO (Nisshin Oil), Migliool (Mitsuba Trading), Bana Sate (Nippon Yushi), Cocona Examples include Ido (Kao), Myritol GM (Henkel Hakusui), TCG (higher alcohol industry), San Fat MCT-6 (Taiyo Chemical), and Factor (RIKEN Vitamin). The content of the medium-chain triglyceride is usually about 50 to 99% by weight, preferably about 80 to 99% by weight, more preferably about 90 to 98% by weight, based on the whole preparation. The weight ratio is usually about 1 to 200 times, preferably about 5 to 100 times, more preferably about 10 to 50 times, and more preferably about 20 to 30 times the weight of the main drug. If the content of the medium-chain fatty acid triglyceride is too large, the desired pharmacological effect may not be obtained due to the low concentration of the active drug, while if the content is too small, sufficient oral absorption is not achieved. Pharmacological effect of No result.

In order to further enhance the oral absorption of the TRH derivative in the present preparation, it is preferable to add lecithin. Examples of lecithin include natural egg yolk lecithin, soybean lecithin, hydrogenated lecithin thereof, synthetic phosphatidylcholine, and the like, and preferably soybean lecithin. When lecithin is added, its content is usually about 0.1 to 20% by weight, preferably about 0.5 to 15% by weight, more preferably about 1 to 10% by weight, based on the whole preparation. %. The weight ratio is usually about 0.1 to 10 times, preferably about 0.5 to 5 times, more preferably about 1 to 3 times the weight of the active ingredient. In the present preparation, lecithin is preferably in a dissolved state. If the lecithin content is too high, lecithin may not dissolve in the medium-chain fatty acid triglycerides and may adversely interfere with drug absorption.

The form of the present preparation is, for example, a liquid, powder, soft capsule, hard capsule, tablet, granule and the like, and preferably a powder, hard capsule and the like. It may also be in the form of a \ WO-type emulsion formed by combining a medium-chain fatty acid triglyceride (preferably ODO) and lecithin.

This preparation can be optionally used with excipients (lactose, starch, microcrystalline cellulose, etc.), binders (hydroxypropylcellulose, etc.), disintegrants (CMC-Na, CMC-Ca, etc.), lubricants (stearin, etc.) Pharmaceutical additives such as magnesium acid), dissolution aids (triethyl citrate, triacetin, etc.), absorption promoters (polycarboxylic acid, oxycarboxylic acid, etc.), stabilizing agents, solubilizing agents, suspending agents, dispersing agents, etc. Can be contained.

The production method of the present preparation is not particularly limited, but usually, the main drug may be dissolved or suspended in medium-chain fatty acid triglyceride. Powders can be prepared using the obtained suspension or the like, or they may be filled in capsules.

The dosage varies depending on the disease state, age, administration route, etc., but is usually about 0.1 to 100 mg / day, preferably about 1 to 20 mg / day as the main drug for adults. It is within the range.

In this formulation, oral absorption is improved by combining medium-chain fatty acid triglyceride with the main drug, and in fact, it is used in various animals such as rats, dogs and mice. The greatest improvement in availability was confirmed. The improvement effect is also apparent in the actual drug efficacy.For example, when this formulation is orally administered to mice pretreated with reserpine, physiological saline without medium-chain fatty acid triglyceride After administration, a rapid rise in rectal temperature was observed compared to preparations dissolved in water or distilled water for injection. The rate of temperature rise when this formulation was administered was about twice or more up to about 2 hours after administration as compared with the case of the formulation without the addition of medium-chain fatty acid triglyceride. However, the effect of increasing the temperature was maintained to a certain extent without a rapid decrease after 2 hours from the administration, and the temperature value at about 7 hours after the administration was almost at the same level as that of the non-added preparation.

Furthermore, in this preparation, the bioavailability was significantly improved by adding a very small amount of lecithin to the medium-chain fatty acid triglyceride.In fact, in the rat, the bioavailability was 30- A 40-fold improvement effect was observed.

As is apparent from these facts, the present preparation has the following characteristics.

(1) Even in small doses of the main drug, it exerts its efficacy quickly and efficiently.

(2) Sustained efficacy is achieved.

(3) Since oral administration is possible, it can be administered without the pain of injections, and home therapy for patients is also possible. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the effect of increasing body temperature after oral administration of a TRH inducer in reserpine-pretreated mice performed in Test Example 3. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to Test Examples and Examples, but the present invention is not limited thereto.

Test example 1

To compare the bioavailability of TRH derivatives, rats treated with jugular vein force (s1 cwistar, 11 weeks old, male, body weight) At 50 to 260 g, N = 4), each of the test compounds shown below was orally administered in an amount of 10 mg / rat in each formulation under fasted conditions. Blood was collected over time after administration, and after plasma separation, the unchanged compound concentration in plasma was quantified by the following HPLC method. Table 1 shows the results.

[HPLC method]

Column YMC P ack AM-302 4.6 mm I D. x 1 50 mm Mobile phase P I C B— 5 ZM e C N = 83 17

Flow rate 1.Om l / min.

UV = 200 nm

[Test compound]

X Het ² ZR ¹ R ²

TRHC * a CHC ONH ₂

Compound A o * b C M e C O NH 2

Compound B 0 * b SM e CONH ₂

Compound C 〇 * b c M e C N

Compound!) O * b c Me Me (Me-methyl)

(Note) Each of the above compounds is described in WO98 / 08867. Compound E

[Prescription] Control 1 (aqueous solution)

1 Omg of the test compound was dissolved in 1 ml of distilled water for injection.

This formulation 1 (ODO suspension)

1 O mg of the test compound was added to 24 O mg of ODO-C (Nisshin Oil), and after ultrasonic irradiation, it was uniformly dispersed by stirring with a magnetic stirrer.

This formulation 2 (ODO suspension with soy lecithin)

Dissolve 12.5 mg of soybean lecithin (Tsuru Lecithin Industrial Co., Ltd., SLP—White SP) in ODO—C (Nisshin Oil) 227.5 mg. 1 Omg of the test compound was added to this solution, and after ultrasonic irradiation, it was uniformly dispersed by stirring with a magnetic stirrer.

(table 1 )

Bioavailability evaluation after oral administration (0-6 hours,%) Meanshi S.D. _ Preparation TRHABCD E_-Control 1 0.1 ± 0.2 0.0 Sat 0.0 0.7 Sat 0.8 0.0 ± 0.0 3.4 1.4 1.4 Sat 0.3 This preparation 1 3.4 ± 1.0

This product 2 3.4 ± 2.3 6.5 Sat 1.7 25.5 Sat 21.1 4.1 ± 3.5 13.2 Sat 4.1 33.7 ± 24.9 (Note) Bioavailability was calculated by adjusting the dose based on the AUC at the time of the intravenous experiment conducted separately. Represents bioavailability.

Compared to the formulation of Control Example 1, the absorption of the TRH derivative was improved about 5-fold in this formulation 1. In the case of Formulation 2 to which lecithin was added, the absorption was further improved, and the absorption improvement effect of TRH was about 30-fold and that of the TRH derivative was up to about 40-fold. Test example 2

10 mg of the above test compound was administered to beagle dogs (body weight: 9-llkg (mean: 10.4 ± 0.7 kg), OMK male (N = 4) and female (N = 2)) Oral doses / kg, fasted, with 25 ml water. After a certain period of time, blood was collected from the forelimb vein. After plasma separation, the unchanged substance concentration in the plasma was quantified by the HPLC method. Table 2 shows the results.

[Prescription]

Formulation 3 (ODO suspension with soy lecithin)

100 mg of soy lecithin (SLP-White SP, manufactured by Tsuruichi Lecithin Industry Co., Ltd.) is dissolved in ODO-C (Nisshin Oil) 180 Omg. The test compound lO Omg was added to this solution, and after ultrasonic irradiation, it was uniformly dispersed by stirring with a magnetic stirrer.

(Table 2)

Bioavailability evaluation after oral administration (0-6 hr,%) Mean S.D.

Formulation Compound B Compound C Compound D

This product 3 19.4 ± 13.0 11.4 ± 3.5 — 42.4 Sat 12.0

(Note) Bioavailability indicates the absolute bioavailability calculated by adjusting the dose based on the AUC at the time of the intravenous experiment conducted separately. Test example 3

Compound A was orally administered to a reserpine-pretreated mouse (s 1 cdd Y, body weight 30-35 g, N = 5) at a dose of 0.2 mol / kg under non-fasting condition (approximately 0.2 ml). Rectal body temperature was measured over time, and an increase in body temperature was used as an index of the pharmacological effect.

[Prescription]

Control 2 (saline solution)

0.7 mg of Compound A was dissolved in 10 ml of physiological saline.

Formulation 4 (OD〇 suspension)

0.7 mg of Compound A was added to 10 ml of the 00〇 solution, and after ultrasonic irradiation, the mixture was stirred with a magnetic stirrer and uniformly dispersed (without lecithin). Figure 1 shows the results. In the formulation of Control Example 2 (one stroke), the body temperature rise was almost the same as that when saline was administered (1-1), whereas with this formulation 4 (-·-), the temperature rise was more rapid than immediately after administration. Was observed. Example 1

The compound A (10 g), Panacet 800 (manufactured by NOF CORPORATION) (100 g) and soybean lecithin (10 g) are thoroughly mixed with a magnetic stirrer, and the mixture is stirred to obtain a suspension. Example 2

15 g of the compound B, 200 g of Miglyol (Mitsuba Trading) and 15 g of soybean lecithin are sufficiently mixed and stirred with a magnetic stirrer to obtain a suspension. This suspension is filled with a capsule machine according to a conventional method to obtain a soft capsule.

Example 3

20 g of the compound C, 400 g of ODO-C (Nisshin Oil) and 3 Og of soybean lecithin are sufficiently mixed and stirred with a magnetic stirrer to obtain a suspension. The suspension is filled with a capsule machine according to a conventional method to obtain a hard capsule.

Example 4

A suspension was obtained by sufficiently mixing and stirring 10 g of the compound D, 200 g of coconado (Kao) and 10 g of soybean lecithin with a magnetic stirrer. Silica (Carplex # 80, Shionogi) was added to this suspension to prepare a powder, which was filled with a capsule machine to obtain a hard capsule. Industrial applicability

The use of this formulation containing medium-chain fatty acid triglycerides improved the oral absorption of TRH derivatives, and as a result, significantly improved bioavailability. By adding even smaller amounts of lecithin, bioavailability was even better. In addition, instead of triglycerides of medium-chain fatty acids, higher fatty acids such as soybean oil and wheat germ oil were used to examine the oral absorption in the same manner, but no sufficient improvement effect was observed, but rather a decrease in medicinal effect was observed. Was done. In general, the TRH derivative has high stability to enzymes in the gastrointestinal tract, and it is considered that the improvement in oral absorption according to the present invention is a result of improving the gastrointestinal mucosal permeability itself of the TRH derivative,

Claims

The scope of the claims

1. An orally administered preparation comprising L-pyroglutamyl-L-histidyl-1-L-prolineamide or a derivative thereof and a medium-chain triglyceride as a main drug.

2. The preparation according to claim 1, further comprising lecithin.

3. The formulation according to claim 2, wherein the lecithin is soy lecithin.

4. The preparation according to claim 1, wherein the medium-chain fatty acid triglyceride is contained in an amount of 1 to 200 times (by weight) the main drug.

5. The preparation according to claim 2, wherein lecithin is contained in an amount of 0.01 to 10 times (weight ratio) the active substance.

6. The main drug has the formula:

(Wherein, H et H et ² represents any group shown below, respectively

(R ¹ is hydrogen or alkyl; X is CH ₂ or 〇)

Z is CH ₂ or S;

R ² is alkyl, one CH ₂ OR ³ , one C〇NHR ⁴ , —C〇OR ⁵ or —CN (R ³ R ⁴ and R ⁵ are each independently hydrogen, optionally substituted alkyl or optionally substituted aralkyl);

Me represents methyl)

The preparation according to claim 1, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof or a hydrate thereof.

7. The method according to any one of claims 1 to 6, wherein the rate of increase in body temperature after oral administration to reserpine-pretreated mice is about twice or more as compared with a preparation containing no medium-chain fatty acid triglyceride and lecithin. Formulation.

8. The formulation according to any one of claims 1 to 6, wherein the bioavailability in a rat is about 30 times or more as compared with a formulation not containing a medium-chain fatty acid triglyceride and lecithin.