WO1999039730A1 - Preparation a administration orale contenant des peptides favorisant la secretion d'hormone de croissance - Google Patents

Preparation a administration orale contenant des peptides favorisant la secretion d'hormone de croissance Download PDF

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Publication number
WO1999039730A1
WO1999039730A1 PCT/JP1998/000529 JP9800529W WO9939730A1 WO 1999039730 A1 WO1999039730 A1 WO 1999039730A1 JP 9800529 W JP9800529 W JP 9800529W WO 9939730 A1 WO9939730 A1 WO 9939730A1
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Prior art keywords
ghrp
water
cellulose
oral preparation
growth hormone
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PCT/JP1998/000529
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English (en)
Japanese (ja)
Inventor
Fumiyoshi Moriya
Akiko Ochiai
Takashi Goto
Makoto Hirayama
Yoshiro Otani
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Kaken Pharmaceutical Co., Ltd.
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Priority to PCT/JP1998/000529 priority Critical patent/WO1999039730A1/fr
Publication of WO1999039730A1 publication Critical patent/WO1999039730A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to an oral preparation containing a growth hormone secretagogue peptide, and more particularly, it has good chemical stability, activates passive transport after oral administration, and suppresses the activity of proteolytic enzymes. It relates to an oral preparation having an excellent ability to secrete growth hormone by improving the absorption of a peptide or a salt thereof (Growth Hormone releasing peptide ⁇ hereafter sometimes abbreviated as GHRP) which promotes the secretion of growth hormone. is there.
  • GHRP Crowth Hormone releasing peptide
  • Growth hormone is a growth-promoting peptide hormone produced by eosinophilic cells in the anterior pituitary gland. When this hormone is deficient, growth hormone secretory short stature and growth hormone secretion deficiency are observed. It causes diseases such as Turner syndrome. In the treatment of these diseases, currently, growth hormone itself is intramuscularly injected at a medical institution about 2 to 3 times a week or self-injected about 6 to 7 times a week subcutaneously. However, since this growth hormone therapy is injection therapy, patients cannot escape the pain of injection, and long-term treatment puts a lot of burden on patients, so less burdensome treatment The development of a law is desired.
  • the growth hormone secretagogue present in the hypothalamus is a peptide having about 40 amino acid residues in humans, and is isolated and purified from human cells, or synthesized using a peptide synthesizer.
  • the method of separation and purification from human cells is limited in quantity, and the synthesis method requires nearly 40 amino acids.
  • the acid must be condensed, the operation is complicated, it takes a long time, and the cost is high.
  • GHRP When the above GHRP is provided as an injection for the treatment of dwarfism, it must be administered frequently for treatment as described above, and as a result, a large burden is imposed on the patient due to pain and going to a hospital. Therefore, in order to solve this problem, it is essential to provide it as an oral preparation.
  • this GHRP is a peptide drug, it frequently interacts with additives that are commonly used. In fact, it was not easy to produce oral preparations that may appear, easily cause discoloration and decrease in content, and maintain long-term chemical stability. In addition, there are problems such as low absorption in the gastrointestinal tract and susceptibility to degradation by proteolytic enzymes. Therefore, it is indispensable to solve these problems in order to provide an oral preparation. Disclosure of the invention
  • the present invention has little interaction with commonly used additives, is chemically stable, has good absorption in the gastrointestinal tract, and is less susceptible to degradation by proteolytic enzymes. It is an object of the present invention to provide an oral preparation containing a growth hormone secretion promoting peptide, which has characteristics such as growth hormone secretion promoting ability.
  • the present inventors have conducted intensive studies to develop an oral preparation containing a growth hormone secretion promoting peptide having the above excellent properties, and as a result, combined GHRP with crystalline cellulose and water-swellable modified cellulose. (1) is chemically stable, and (2) absorbs digestive juices after oral administration to form a slurry in which the concentration of GHRP is partially high.
  • the present invention is characterized in that it comprises (A) a peptide or a salt thereof that promotes the secretion of growth hormone, and (B) at least one selected from crystalline cellulose and water-swellable modified cellulose.
  • the present invention provides an oral preparation containing a growth hormone secretion promoting peptide.
  • FIG. 1 is a diagram showing a comparison of the maximum blood levels of secreted growth hormone when the preparations of Examples 2, 3, and 4 and Control 3 were administered to humans.
  • FIG. 2 shows a comparison of the area under the blood concentration of secreted growth hormone when the preparations of Examples 2, 3, and 4 and Control 3 were administered to humans. Best mode for carrying out the invention.
  • the peptide in GHRP used as the component (A) may be any peptide having a pharmacological activity for promoting the secretion of growth hormone from the pituitary gland.
  • the number and origin of the groups are not particularly limited, but include pharmacological activity and absorbability.
  • a peptide having 3 to 10 amino acid residues and / or amino acid derivative residues or a salt thereof is preferable.
  • amino acid derivative forming the above-mentioned amino acid derivative residue examples include alkyl-substituted tryptophan, ⁇ -naphthylalanine, hy-naphthylalanine, 3,4-dihydroxy phenylalanine, methyl valine and the like.
  • Amino acids and amino acid derivatives include both L-form and D-form.
  • the salt in GHRP is an acid addition salt.
  • the acid capable of forming the acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, and nitric acid, formic acid, acetic acid, and the like.
  • organic acids amino acids such as aspartic acid and glutamic acid, those capable of forming a pharmaceutically acceptable acid addition salt are appropriately selected.
  • Examples of GHRP having 3 to 10 amino acid residues and / or amino acid derivative residues include, for example, D-alanyl-3- (naphthylene-1-yl) -D-aralanyl L-aralanyl-L-tributophyl-D L-Lysinamide, L-Histidyl 2-methyl-D-tryptofil-L-aranil L-Tryptofil-D-Fenral-L-Lu L-Lysinamide (Hexarelin, Hexarelin), L-Farranil-L —Histidyl-1 3— (Naphthylene 1-2-yl) 1—D-Aranyl-L-Aranil— L-Tryptofil-D—Fenryl 2-L-L-Lysine amide, L-Histidyl-D-Tryptofil-L—Aranil-L D-phenylalanyl L-Jinamide and D-aralanyl 12-
  • GHRP-2 D-aralanyl 3- (naphthylene-1-yl) -D-aralanyl-L-aralanyl-L-tryptofil-D-fenyaralanil — L-lysine amidoni hydrochloride
  • GHRP may be used alone or in combination of two or more as the component (A).
  • the component (B) at least one selected from crystalline cellulose and water-swellable modified cellulose is used.
  • the crystalline cellulose refers to a white to gray-white color obtained by partially depolymerizing (hydrolyzing) heat cellulose with a mineral acid to remove an amorphous region, and purifying and drying the cellulose in the crystalline region. It is a crystalline powder.
  • Such crystalline cellulose can be easily obtained as a commercial product such as “Avicel” (trade name, manufactured by Asahi Kasei Kogyo Co., Ltd.).
  • the crystalline cellulose coated with the water-soluble polymer compound on the particle surface is referred to as colloidal type crystalline cellulose
  • the water-soluble polymer compound first swells and dissolves to disintegrate the individual particles, which are secondary aggregates, to form a network structure in which fine cellulose crystals, which are the constituent units, have become colloidal dispersions.
  • a water-soluble polymer compound acts as a protective colloid. Therefore, when incorporated into GHRP, the activity of proteolytic enzymes is effectively inhibited as described below. Particularly preferred.
  • Such crystalline cellulose whose particle surface is coated with a water-soluble polymer compound can be obtained as a colloidal grade of “Avicel”.
  • the water-swellable modified cellulose is cellulose that has been chemically modified to impart water-swellability.
  • the water swelling property refers to a property of being substantially insoluble in water when introduced into water, but of absorbing water and increasing in volume.
  • those immersed in water at 25 ° C. and pH 7 for 5 hours and having a water swelling degree that swells 1.15 times more preferably are used.
  • More preferable water swelling degree is The water swelling degree is 1.3 to 20 times, particularly preferably 1.3 to 20 times.
  • the modification method may be any method as long as it has the above-mentioned degree of water swelling and is acceptable as a pharmaceutical additive, and is not particularly limited.
  • alkylation, carboxymethylation, hydroxyalkylation, Modification means such as substituted or unsubstituted aminoalkylation.
  • the modified cellulose obtained by the above-mentioned various modification means modified to an inorganic or organic salt is also included in the modified cellulose of the present invention.
  • Preferred examples of such water-swellable cellulose include carboxymethylcellulose, calcium carboxymethylcellulose, sodium cross-carboxymethylcellulose, and low-substituted hydroxypropylcellulose.
  • sodium carboxymethylcellulose is a crosslinked polymer of sodium carboxymethylcellulose, and is easily available as a commercial product such as "Ac-Di-SoI” (trade name, manufactured by Asahi Kasei Kogyo Co., Ltd.). be able to.
  • the low-substituted hydroxypropylcellulose has a hydroxybutoxy group obtained by adding propylene oxide to a part of the hydroxyl groups of cellulose, and has a content of about 5 to 20% by weight. If the content of the hydroxypropoxy group is less than 5% by weight, water swelling property will not be sufficiently provided, and if it exceeds 20% by weight, it will be easily soluble in water, and the object of the present invention may not be achieved.
  • the component (B) one kind of the above-mentioned crystalline cellulose / water-swellable modified cellulose (hereinafter sometimes collectively referred to as water-swellable celluloses) is used. Or two or more of them may be used in combination.
  • the oral preparation of the present invention has the following effects by blending the water-swellable cellulose of the component (B) with the GHRP of the component (A).
  • GHRP GHRP-2
  • a buffer solution with a pH of 2 to 6.8 GHRP mixed with crystalline cellulose or water-swellable modified cellulose
  • a water-soluble additive is added.
  • crystalline cellulose or water-swellable modified cellulose absorbs the buffer solution and swells to form a slurry, thereby suppressing the elution of GHRP into the buffer solution.
  • the GHRP concentration is maintained at a high level for a relatively long time in a slurry under a gentle stirring condition.
  • GHRP mixed with crystalline cellulose, especially colloidal-type crystalline cellulose or water-swellable modified cellulose, especially carboxymethylcellulose has the optimal activity of trypsin and chymotrypsin, which are prone to degrade proteolytic enzymes, especially GHRP.
  • GHRP forms an adsorption equilibrium with colloidal-type crystalline cellulose or carboxymethylcellulose, and there is a tendency to inhibit the activity of proteolytic enzymes, which is thought to be due to steric hindrance. From this, it is considered that when the formulation of the present invention is orally administered, GHRP remains in the gastrointestinal tract as an unchanged form without undergoing degradation by proteolytic enzymes, and the absorbability is improved.
  • the water-swellable modified cellulose is carboxymethylcellulose, since it disperses in water, it becomes acidic, so it may shift the pH in the gastrointestinal tract to the acidic side and reduce the activity of proteases. .
  • At least one additive selected from the group consisting of citric acids can be appropriately selected and contained depending on the form of the preparation.
  • the weight ratio of the component (A) GHRP to the component (B) in the oral preparation of the present invention should be appropriately selected according to the form of the preparation, but is generally 1: 1.5 to 200: 200. , Preferably 1: 2 to: L00, more preferably 1: 3 to 50.
  • the form of the oral preparation of the present invention is not particularly limited. Preparations, granules, capsules, powders (fine granules), dry syrups, syrups, pills, suspensions, soft capsules, etc. are possible.
  • GHRP of the present invention In the oral preparation of GHRP of the present invention, by mixing microcrystalline cellulose and water-swellable modified cellulose with GHRP, a partial high concentration region of GHRP by the slurry is formed, and the degradation by proteolytic enzymes is delayed, In particular, when the water-swellable modified cellulose is carboxymethylcellulose, since it itself is acidic, the activity of the protease is reduced, and as a result, the degradation of GHRP by the protease is suppressed and the absorbability is improved. Is done.
  • Table 1 below shows the manufacturers and trade names (standards) of the materials used.
  • a liquid binder was added to the mixed powder, kneaded, and granules were produced using an extrusion granulator equipped with a screen having a hole diameter of 0.8 mm. After drying at 50 ° C for 3 hours, the mixture was sieved using 12-mesh and 42-mesh sieves to obtain granules.
  • GHRP-21 Og and 974 g of mannitol were mixed with a stirring granulator to obtain a mixed powder.
  • 16 g of hydroxypropylcellulose was dissolved in 20 ml of isopropanol to obtain a liquid binder.
  • a liquid binder was added to the mixed powder, kneaded, and granules were produced using an extrusion granulator equipped with a screen with a 0.8 mm hole. After drying at 50 ° C for 3 hours, the mixture was sieved using 12-mesh and 42-mesh sieves to obtain granules (hereinafter, referred to as reference 1).
  • GHRP-2 1.1 g Microcrystalline cellulose (Avicel PH-30 1) 12.1 g, lactose 2 g, talc 0.6 g and low-substituted hydroxypropylcellulose (LH-11) 2 g in a mortar After mixing, 0.2 g of magnesium stearate was further added and mixed to obtain a mixed powder.
  • the above-mentioned mixed powder was compression-molded to a tablet of 18 Omg with a molding machine in which a mortar having a diameter of 8.0 mm and a goishi-shaped punch were set to obtain tablets.
  • GHRP-2.1 g, colloidal crystalline cellulose 40 g, sucrose 10 g, aspartame 4 g, D-mannitol 38.7 g, citrate 4 g and sodium chloride 1 g were mixed with a mixing granulator using a stirring granulator. did. Separately, 1.2 g of hydroxypropyl cellulose was dissolved in 4 Oml of isopropanol to obtain a liquid binder. Add a liquid binder to the mixed powder, granulate and dry at 50 ° C for 3 hours. The mixture was sieved using a mesh sieve to obtain a powder.
  • GHRP- 2 1 1 mg Lactose 84 1 7 mg Carboxymethyl cellulose 45 7 mg Hydroxypropyl cellulose 18 3 mg Methacrylic acid copolymer 60 7 mg Hydroxypropyl methylcellulose 6 8 mg Macrogol 6000 3 mg Magnesium stearate 4 —5 m
  • GHRP—21.2 g, lactose 921.8 g and carboxymethylcellulose 50 g were mixed into a powder mixture using a stirring granulator. Separately, 20 g of hydroxypropyl cell mouth was dissolved in 20 Oml of isopropanol to obtain a liquid binder.
  • a liquid binder was added to the mixed powder, kneaded, and granules were produced using an extrusion granulator equipped with a screen having a 0.8 mm hole diameter. After drying at 50 ° C for 3 hours, the mixture was sieved using 16-mesh and 30-mesh sieves to obtain granules.
  • D-mannitol 68 4 mg talc 6 mg carboxymethylcellulose 175 mg hydroxypropylcellulose 16 mg magnesium stearate —1 _8 _ mg ⁇
  • GHRP-2 2 g
  • microcrystalline cellulose Avicel PH-30 60 g
  • D-mannitol 68.4 g D-mannitol 68.4 g
  • talc 6 g carboxymethylcellulose 17.
  • a liquid binder was added to the mixed powder, and the mixture was granulated to produce granules. After drying at 50 ° C for 3 hours, the mixture was sieved using a 42-mesh sieve, and 1.8 g of magnesium stearate was added as a lubricant, followed by mixing using a plastic bag.
  • a film corresponding to was applied using a coating device to obtain a film-coated tablet.
  • a liquid binder was added to the mixed powder, kneaded, and granules were produced using an extrusion granulator equipped with a screen having a 0.8 mm hole diameter. After drying at 50 ° C for 3 hours, the mixture is sieved using a 12-mesh and a 42-mesh sieve, and an amount equivalent to 5% by weight of light anhydrous silica is added as an anti-agglomeration agent and mixed in a plastic bag. Granules were obtained.
  • a liquid binder is added to the mixed powder, granulated, dried at 50 ° C for 3 hours, and then sieved using a 42-mesh sieve. Was added and mixed in a plastic bag to obtain a powder.
  • Granule formulation (in 100 Omg) GHRP-2 10 mg carboxymethyl cellulose 30 mg
  • a liquid binder was added to the mixed powder, kneaded, and granules were produced using an extrusion granulator equipped with a screen having a 0.8 mm hole diameter. After drying at 50 ° C for 3 hours, the mixture is sieved using a 12-mesh and a 42-mesh sieve, and an amount equivalent to 5% by weight of soft anhydrous calcium acid is added as an anti-agglomeration agent and mixed in a plastic bag. Granules were prepared.
  • Colloidal type microcrystalline cellulose 2 0.1 mg was added to Omg and suspended to prepare a suspending agent.
  • a 0.1% by weight aqueous solution of GHRP-2 (0.1 ml) was added to 0.6 mg of crystalline cellulose and suspended to prepare a suspending agent.
  • GHRP-2 Aspartame 45 mg, D-mantol 894 mg, hydroxymethylcellulose 16 mg, light caffeic anhydride 5 mg, carboxymethylcellulose 30 mg and 0.4% by weight GHRP-2 aqueous solution 2.5 or 5 ml (GHRP-2 10 or 2 Omg) to give a GHRP-2 / excipient mixture.
  • GHRP-2 aqueous solution 2.5 ml (GHR P-2 10 mg) Carboxymethylcellulose 10-90 mg
  • Single excipient mixed powder 900-980 mg A total of 1000 mg of aspartame, 0.936 g of D-mannitol, 18.628 g of hydroxymethylcellulose, 16.6 g of hydroxymethylcellulose, and 5.2 g of light caffeic anhydride were mixed using a mortar to obtain a mixed powder of the excipient. 900-980 mg of this excipient mixed powder, 10-9 Omg of carboxymethylcellulose and 2.5 ml of 0.4% by weight GHRP-2 aqueous solution (1 Omg of GHRP-2) were mixed to give GHRP-2 / immobilization. Agent mixture.
  • GHRP-2 aqueous solution 5.
  • Oml (GHRP-2 20mg) Carboxymethylcellulose 10 ⁇ 90mg
  • Example 1 The lg of each of the granules of Example 1 and Comparative Example 1 (Control 1) (containing 10 mg of GHRP-2 each) was used as a test solution, and a buffer solution of pH 1.2 (Japanese Pharmacopoeia, 1st solution) was used as a test solution. (50 rpm). Table 2 shows the results.
  • Example 13- To the suspension of L6 and the aqueous solution of Comparative Example 3 were added Tris-HCl buffer 801, pH 8.0, and Tris-HCl buffer 201 (20 units) in which trypsin was dissolved. After 0.5, 1, and 2 hours, an aqueous 10% by weight aqueous solution of TCA (trichloroacetic acid) was added to stop the enzyme reaction. Hydrochloric acid / sodium chloride 0.9 mL of aqueous solution was added to desorb GHHP-2 adsorbed on water-insoluble cellulose, and the precipitate was centrifuged. The mobile phase 100 1 was added to prepare a sample solution.
  • Tris-HCl buffer 801, pH 8.0 Tris-HCl buffer 201 (20 units) in which trypsin was dissolved. After 0.5, 1, and 2 hours, an aqueous 10% by weight aqueous solution of TCA (trichloroacetic acid) was added to stop the enzyme reaction. Hydrochloric acid / sodium chloride 0.9 m
  • 501 of an aqueous solution (lmg / lml) of a cryopreserved standard product was taken, 50 zl of an internal standard solution was added, and a mobile phase 7001 for high performance liquid chromatography was further added to make a standard solution.
  • the amount of remaining GHRP-2 in the sample solution and the standard solution was determined using high performance liquid chromatography.
  • High-performance liquid chromatography was performed under the following conditions: High-performance liquid chromatography equipment: LC-6A and LC-1OA (Shimadzu Corporation)
  • Example 13 16 As can be seen in Table 3, when compared with the GHRP-2 aqueous solution of Comparative Example 3, the suspension of Example 13 16 containing the water-swellable cellulose in an amount generally used for oral preparations showed that trypsin Was confirmed to be delayed.
  • carboxymethylcellulose, carboxymethylcellulose calcium, and colloidal type microcrystalline cellulose showed a remarkable effect of delaying decomposition.
  • Example 23 Each of the preparations obtained in Example 23 and Comparative Example 2 (Control 3) was orally administered to humans in an amount containing 11 mg of GHRP-2, and secreted by absorption of GHRP-2 The blood kinetics of growth hormone were evaluated and compared (six in control 3 and five in example 2 34). In addition, Example 3 was administered after being sufficiently stirred and suspended in 5 Oml of water as a dry syrup at the time of administration. The results are shown in FIGS. FIG. 1 and FIG. 2 are diagrams showing a comparison of the maximum blood concentration of growth hormone and the area under the blood concentration when the preparations of Example 24 and Control 3 were administered to humans, respectively.
  • the average growth hormone secretion of 6 subjects from control 3 without water-swellable celluloses was 22 / g / L at the maximum blood concentration (Cmax) and 1909 / g at the area under the blood concentration (AUC). min / L.
  • the average growth hormone secretion of each of the five subjects in Examples 2, 3, and 4 was 67.7, 50.5, and 65.
  • the area under the blood concentration (AUC) was 5378, 4152, and 4854 g ⁇ min / L. Therefore, the formulation containing crystalline cellulose or water-swellable modified cellulose in the formulation of GHRP-2 has a maximum blood concentration (Cmax) of about 2.3 to 3.0 compared to the formulation of Comparative Example 2.
  • Cmax maximum blood concentration
  • the growth hormone release effect was approximately 2.2 to 2.8 times that of the area under blood concentration (AUC).
  • Examples 2, 3, and 4 show the effects shown in Test Examples 1 and 2 by adding water-swellable celluloses such as crystalline cellulose, colloidal-type crystalline cellulose, and carboxymethylcellulose. It is considered that the absorption of GHRP-2 was improved by the treatment.
  • Examples 5 and 6 which are oral preparations containing GHRP-2, water-swellable celluloses and additives chemically stable with GHRP-2, and for the purpose of improving the stability of GHRP-2
  • a stability test was conducted for 30 days at 7, 8 and 60 ° C, 40 ° C, and 75% relative humidity. In this test, changes in GHR P-2 content in each product were investigated by observing the color change of each product by the naked eye and using high performance liquid chromatography.
  • the middle row shows the amount of GHRP-2 contained in 1 tablet or 1 g of the drug product
  • the lower row shows the residual ratio when the amount of GHRP-2 at the start of the test is 100%.
  • the amount of GHRP-2 in the sample solution was determined for the sample solution and the standard solution using high performance liquid chromatography, and the adsorption rate of GHRP-2 to water-swellable celluloses was calculated from this value.
  • the GHRP-2 / excipient mixture of Example 17 was prepared using the buffers of ⁇ 1, 2, 3, 4, 5, 6.5 and 7.2. The adsorption rate of carboxymethylcellulose was examined.
  • the adsorption test was performed by the following method.
  • the amount of GHRP-2 in the sample solution was determined from the absorbance at 278 nm of the sample solution and the standard solution using a spectrophotometer, and the adsorption rate of GHRP-2 to carboxymethyl cellulose was determined from this value. Table 6 shows the results.
  • Test Example 6 it was found that the adsorption rate of GHRP-2 to carboxymethyl cellulose under pH 4 or higher was high. Therefore, in this test example, the appropriate mixing ratio of GHRP-2 and carboxymethylcellulose was examined by the adsorption rate of GHRP-2 to carboxymethylcellulose at pH 6.5.
  • the adsorption test was performed by the following method.
  • the GHRP-2Z excipient mixtures obtained in Examples 18 and 19 were each added to a phosphorus buffer (pH 6.5, pH 7.2) and stirred for 1 hour. This suspension was filtered through a 0.45 membrane filter, and the filtrate was adjusted to exactly 50 ml by adding water to 5 ml to prepare a sample solution. Separately, 2.5 or 5.0 ml of a 0.4% by weight GHRP-2 aqueous solution was taken and made up to exactly 50 ml with water. 5 ml of this solution was taken, adjusted to exactly 50 ml with water, and used as a standard solution.
  • a phosphorus buffer pH 6.5, pH 7.2
  • the amount of GHRP-2 in the sample solution was determined from the absorbance at 278 nm of the sample solution and standard solution using a spectrophotometer. The adsorption rate of GHRP-2 on the loin was determined. C showing the results in Table 7
  • CMC carboxymethylcellulose
  • the adsorption rate of GHRP-2 to carboxymethylcellulose was as follows: the amount of carboxymethylcellulose was 3 Omg or 6 Omg per GHRP-21 Omg or 2 Omg. In the vicinity (GHRP-2 and carboxymethylcellulose mixture ratio 1: 3), it increased sharply, and thereafter showed a gradual increase. Considering the ease of manufacturing in oral formulations, it is considered that the appropriate ratio of carboxymethylcellulose to GHRP-2 is around 1: 3. For dosage forms such as powders (granules), which are easy to manufacture, it may be possible to mix 1: 200. Industrial applicability
  • the oral preparation containing a growth hormone secretion promoting peptide of the present invention has good chemical stability, activates passive transport after oral administration, suppresses the activity of proteolytic enzymes, and reduces the secretion of growth hormone. It is an oral preparation with enhanced growth hormone secretion ability with improved absorption of the peptide or its salt that promotes.

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Abstract

L'invention concerne des préparations à administration orale contenant des peptides favorisant la sécrétion d'hormone de croissance. Ces préparations présentent une absorbabilité améliorée des peptides, qui présentent une stabilité chimique élevée, activent le transport passif après l'administration et inhibent les protéases, favorisant ainsi la sécrétion d'hormone de croissance. Ces préparation contiennent (A) des peptides capables de favoriser la sécrétion d'hormone de croissance ou des sels de ces peptides et (B) de la cellulose cristalline ou gonflable à l'eau.
PCT/JP1998/000529 1998-02-09 1998-02-09 Preparation a administration orale contenant des peptides favorisant la secretion d'hormone de croissance WO1999039730A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
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WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
JP2008120771A (ja) * 2006-11-08 2008-05-29 Bhn Kk 便秘改善剤
EP2457925A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Procédé pour la préparation d'un modulateur macrocyclique du récepteur de ghréline et intermédiaires
US8192719B2 (en) 2006-02-18 2012-06-05 Aeterna Zentaris Gmbh Methods and kits to diagnose growth hormone deficiency by oral administration of EP 1572 or EP 1573 compounds
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
US8992980B2 (en) 2002-10-25 2015-03-31 Boehringer Ingelheim Vetmedica Gmbh Water-soluble meloxicam granules
US9795568B2 (en) 2010-05-05 2017-10-24 Boehringer Ingelheim Vetmedica Gmbh Low concentration meloxicam tablets
US10548901B2 (en) 2004-02-23 2020-02-04 Boehringer Ingelheim Vetmedica Gmbh Meloxicam for the treatment of respiratory diseases in pigs

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JPH05509105A (ja) * 1990-07-24 1993-12-16 ポリゲン　ホールディング　コーポレイション 成長ホルモン放出活性を有するポリペプチド化合物
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Cited By (12)

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Publication number Priority date Publication date Assignee Title
US8992980B2 (en) 2002-10-25 2015-03-31 Boehringer Ingelheim Vetmedica Gmbh Water-soluble meloxicam granules
US9066955B2 (en) 2002-10-25 2015-06-30 Boehringer Ingelheim Vetmedica Gmbh Water-soluble meloxicam granules
US9849137B2 (en) 2002-10-25 2017-12-26 Boehringer Ingelheim Vetmedica Gmbh Water-soluble meloxicam granules
US10548901B2 (en) 2004-02-23 2020-02-04 Boehringer Ingelheim Vetmedica Gmbh Meloxicam for the treatment of respiratory diseases in pigs
EP2457925A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Procédé pour la préparation d'un modulateur macrocyclique du récepteur de ghréline et intermédiaires
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
US8192719B2 (en) 2006-02-18 2012-06-05 Aeterna Zentaris Gmbh Methods and kits to diagnose growth hormone deficiency by oral administration of EP 1572 or EP 1573 compounds
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
JP2008120771A (ja) * 2006-11-08 2008-05-29 Bhn Kk 便秘改善剤
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
US9795568B2 (en) 2010-05-05 2017-10-24 Boehringer Ingelheim Vetmedica Gmbh Low concentration meloxicam tablets
US9943486B2 (en) 2010-05-05 2018-04-17 Boehringer Ingelheim Vetmedica Gmbh Low concentration meloxicam tablets

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