JPH09208485A - Scarcely water-soluble composition of peptide/protein medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain scarcely water-soluble composition having a peptide/protein medicine and EDTA, excellent in long-lasting releasability and chemical stability, and useful as a pharmaceutical agent. SOLUTION: This scarcely water-soluble composition is obtained by dissolving a peptide or protein agent (e.g. salmon calcitonin) having at least one amino acid residual group selected from Lys and Arg, and EDTA (e.g. disodium edetate) in an aqueous solvent and subsequently allowing the obtained aqueous solution to stand until the composition is obtained. The composition contains 2.5-5mg of EDTA based on 5-10mg of the peptide or protein agent, and >=1.0mg to <= the saturating amount of the peptide or protein agent and >=5mg of EDTA based on 1ml of the aqueous solvent. The composition can be formulated into an injection, a nasal drug, a transpulmonary drug or an oral drug, and a dose is 0.1×g to 50mg in terms of a calcitonin e.g. when the calcitonin is used as the peptide or protein agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a poorly water-soluble composition of a peptide / proteinaceous drug. More specifically, the present invention has excellent sustained release and / or chemical stability,
The present invention relates to a poorly water-soluble composition comprising a peptide / protein drug and EDTA.

[0002]

2. Description of the Related Art With the progress of biotechnology, peptide / protein drugs have been widely used for the purpose of medical treatment. Most of the administration methods of these drugs are insulin and growth hormone. As is represented by the above, it is a frequent injection administration. However, frequent injection administration causes considerable distress to the patient, and eventually leads to a decrease in medication compliance.
It is a major medical problem. Further, many of these peptide / protein drugs are chemically unstable, which also poses a serious problem in clinical use. Therefore, as a measure to reduce the number of frequent administrations, which is the first major problem in the past, the development of a formulation that can maintain the blood concentration for a long time by a single administration, that is, a sustained-release formulation, has been actively pursued. Has been done. As such preparations, subcutaneous or intradermal injections and implants using various biocompatible and biodegradable polymers as bases have been studied, and polylactic acid / polyglycolic acid copolymers ( PLGA) is mainly studied. However, in the use of biocompatible and biodegradable polymers in sustained release formulations, it is difficult to maintain stable release in vivo, burst release occurs at the initial stage of administration, and it is complicated due to industrialization. As a formulation of some peptide / protein drugs that have problems such as the need for manufacturing facilities, and are not reflected in the drug efficacy due to the nature of the drug even if there are problems of stable release and initial burst release Although used, other peptide / protein drugs are still in the research stage and have not been commercialized. Other biocompatible and biodegradable polymers include collagen and hyaluronic acid, but the actual situation is almost the same as PLGA.

Furthermore, a method of extending the half-life of peptide / protein drugs in blood is also considered as a kind of sustained-release preparation, for example, polyethylene glycol (PEG).
This method is mainly exemplified by a method of hybridizing a high molecular weight compound such as the above with a peptide / protein drug by an irreversible bond. However, this method has various problems such that the activity in a unit unit is lower than that of the peptide / proteinaceous drug itself, and the antigenicity is more likely to occur. At present, it has not been put into practical use. Further, in the case of this preparation, it is necessary to administer injection or drip infusion into a vein or an artery, which is one of the causes that have been put to practical use only for some peptide / protein drugs.

[0004] In addition, another major problem is the active preparation of pharmaceutical preparations for improving the chemical stability of peptide / protein drugs. It is generally known that freeze-dried peptide / protein drugs are stable, but it may be further stabilized by adding a protein such as human albumin or a saccharide such as mannitol during the freeze-drying. Known (for example, JP-A-63-5)
No. 028). In addition, a method of stabilizing by increasing the viscosity of the peptide / protein drug aqueous solution with a thickener such as gelatin or hydroxymethyl cellulose (JP-A-61-282320), and benzal chloride for preventing decomposition by microorganisms A method of adding a preservative such as ruconium to an aqueous solution of a peptide / protein drug (JP-A-59-59)
No. 89619), some peptide / protein drugs are unstable due to metal ions, and therefore, a chelating agent for metal ions such as EDTA is added to an aqueous peptide / protein drug solution (Pharmaceutical Biotechnology Vol. 5).
“Stability and Characterrization of Protein and P
eptide Drugs “Plenum Publishing Corp.) and the like are known.

By the way, JP-A-59-130820 discloses a liquid composition for intranasal administration comprising calcitonin and a surface active agent, and this liquid composition further comprises EDTA.
Although it is described that a preservative such as disodium can be added, all such liquid compositions are specifically provided in a solution state, and the blending amount of calcitonin and disodium EDTA in the liquid composition is 1 ml of the solution. And 0.08 mg and 0.1-2.0 mg, respectively, and as described in the examples, the calcitonin concentration in the liquid composition was 0.1 m from the activity of calcitonin.
It is considered to be less than g / ml. Furthermore, JP-A-2-
In 306921, an aqueous pharmaceutical composition comprising calcitonin and EDTA or a pharmaceutical composition obtained by freeze-drying the same is superior in stability to a composition obtained by a conventional stabilization method. It is described that it is different from the chelating effect of metal ions by EDTA.

[0006]

However, as described above, as a sustained-release formulation for peptide / protein drugs, a sustained-release formulation of the type utilizing a biocompatible, biodegradable polymer, a polymer and a hybrid. There are various problems with the type of sustained release preparations. Therefore, a sustained-release preparation without such problems is desired.
In addition, as a method for improving the chemical stability of peptide / protein drugs, the above-mentioned method is tentatively recognized as an improvement in stability, but this is by no means sufficient, and peptide / protein drugs are used as preparations. At present, there is a demand for a stabilizing method that can achieve long-term stability at room temperature suitable for the above. Therefore, an object of the present invention is to provide a sustained-release preparation of a peptide / protein drug, which does not necessarily require a biocompatible or biodegradable polymer or polymer hybrid. Alternatively, the object of the present invention is to provide a sustained-release preparation of a peptide / protein drug, which can be administered by subcutaneous or intradermal injection, intravenous or arterial injection, mucosal administration of nasal mucosa, pulmonary mucosa and the like. Alternatively, the object of the present invention is not necessarily required to have biocompatible and biodegradable polymers and polymer hybrids, and subcutaneous or intradermal injection administration, intravenous or arterial injection administration, nasal mucosa, pulmonary mucosa, etc. The present invention provides a sustained-release preparation of peptide / protein drug capable of mucosal administration. Furthermore, an object of the present invention is to provide a formulation of a peptide / protein drug with improved chemical stability.

Therefore, the present inventors have proposed, as a sustained-release preparation for peptide / protein drugs, a novel sustained-release preparation that does not rely on biocompatible or biodegradable polymers or polymer hybrids, or a conventional sustained-release preparation. In comparison with the above, an intensive study was conducted on the improved method for stabilizing peptide / protein drugs. As a result, surprisingly, a peptide, which can be produced by, for example, dissolving a peptide proteinaceous drug and EDTA in an aqueous solvent and then leaving the obtained aqueous solution until a sparingly water-soluble composition is obtained. Protein drugs and E
A poorly water-soluble composition comprising DTA can release a peptide / proteinaceous drug from the composition continuously at a constant rate, and even when it is actually administered in vivo by various administration methods, the peptide / proteinaceous drug is kept constant. The present invention has been completed by finding that the peptide / protein drug can be continuously released at a high rate and that the peptide / protein drug has excellent stability.

[0008]

Means for Solving the Problems That is, the present invention relates to a peptide / protein drug as well as a peptide / protein consisting of EDTA.
A poorly water-soluble composition of a protein drug, and a pharmaceutical preparation comprising the poorly water-soluble composition and a pharmaceutically acceptable carrier.

As the peptide / protein drug used in the present invention, all known peptide / protein drugs can be used. According to the findings of the present inventors, the peptide / protein drug and EDTA constituting the present invention are
at least 1 amino acid residue selected from s and Arg
It is presumed that the peptide / protein drug having the above has particularly easy chelation. Therefore, the peptide / protein drug of the present invention has at least one amino acid residue selected from Lys and Arg in its primary structure. It is preferable to use peptide / protein drugs.
The number of amino acid residues selected from such Lys and Arg is not particularly limited as long as it is 1 or more, and any one or more of Lys or Arg and a combination of Lys and Arg may be used. It is presumed that a larger number forms a stronger chelate, which is preferable. Moreover, these Ly in such peptide / protein drugs are used.
The positions of the s and Arg residues may be such that they can form a chelate between the peptide / protein drug and EDTA.

Even with such peptide / protein drugs,
The number of amino acid residues in its primary structure is preferably in the range of 10 to 500, and specific examples of such peptide / protein drug include calcitonin such as salmon calcitonin, human calcitonin, eel calcitonin, and elcitonin. Calcitonin gene-related peptide (CGR
P), somatostatins, growth hormone releasing factor (G
RF) s, endothelins, endorphins, interleukins, substance Ps, glucagons, glucagon-like peptides, adrenocorticotropic hormones, corticotropin-releasing factors, interferons, insulins, growth hormones, growth hormone release Hormones,
Erythropoietins, granulocyte colony formation stimulating factors,
One or more peptide / protein drugs selected from the group consisting of macrophage formation stimulating factors can be mentioned.

In the present invention, calcitonin such as salmon calcitonin, human calcitonin, and eel calcitonin means calcitonin such as salmon calcitonin, human calcitonin, eel calcitonin, and derivatives thereof, and other peptide / protein drugs. Also in the case of, each peptide / proteinaceous drug and its derivative are similarly included, and here, for example, a “derivative” in calcitonin such as calcitonin and its derivative means a peptide in the conventional field such as elcitonin.
What is known as a derivative of proteinaceous drug,
Derivatives of other peptide / protein drugs other than calcitonin are also defined in the same manner. Among these, as the peptide / protein drug of the present invention, salmon calcitonin, human calcitonin, eel calcitonin,
Examples include calcitonin such as elcitonin, calcitonin gene-related peptide (CGRP), somatostatin, growth hormone releasing factor (GRF), and one or more peptide / protein drugs selected from the group consisting of insulins. .

Examples of the EDTA used in the present invention include edetic acid, edetate disodium, edetate calcium disodium and the like, and one or more of them can be used. In the poorly water-soluble composition of the present invention, the peptide / protein drug and E
DTA is presumed to form a chelate. Therefore, the compounding amount of the peptide / protein drug and EDTA in the poorly water-soluble composition of the present invention is, for example, 5 mg to 10 mg of the peptide / protein drug and EDTA.
2.5 mg to 5 mg is preferred.

The peptide / protein drug of the present invention and E
The sparingly water-soluble composition of a peptide / protein drug comprising DTA is obtained by, for example, dissolving a predetermined amount of the peptide / protein drug and a predetermined amount of EDTA in a predetermined amount of an aqueous solvent, and then dissolving the obtained aqueous solution. It can be produced by leaving it until a poorly water-soluble composition is obtained. The method of dissolving the peptide / protein drug and EDTA in an aqueous solvent includes a method of dissolving the peptide / protein drug and the solid of EDTA in an aqueous solvent, and a method of dissolving the peptide / protein drug and the aqueous solution in a solvent. EDT dissolved in a solvent
The method of mixing with A etc. is mentioned. As such an aqueous solvent, all pharmaceutically acceptable aqueous solvents can be used, and specifically, distilled water for injection, distilled water, sterilized distilled water and the like, particularly preferably, distilled water for injection. Is.
Further, a buffer solution containing phosphate, acetate, citric acid, etc. in the distilled water may be used. Also, the pH is not particularly limited as long as the peptide / protein drug is in a stable range, but is preferably in the range of pH 4 to pH 10.

The predetermined amount means the peptide of the present invention.
It is an amount required to prepare a poorly water-soluble composition consisting of a protein drug and EDTA. For example, when the poorly water-soluble composition is produced by the above-mentioned production method, the peptide of the present invention is usually used at room temperature. An amount within the respective saturated solubilities of the proteinaceous drug and EDTA dissolved in the aqueous solvent can be used, and specifically, 1 mg of the peptide / proteinaceous drug per saturated aqueous solvent to the saturated solubility or less,
0.5 mg to 100 mg of EDTA, preferably 1 mg to 100 m of peptide / protein drug per 1 ml of an aqueous solvent.
Below gram, EDTA 0.5mg-50mg can be mentioned. For example, when calcitonin is used as the peptide / protein drug, calcitonin 1.0 mg or more and saturated solubility or less, EDTA 0.5 m / ml in an aqueous solvent 1 ml.
It is preferable to use g or more, and more preferably, 1 mg to 100 mg of calcitonin and E to 1 ml of the aqueous solvent.
DTA is 0.5 mg to 150 mg. In the above-mentioned production method, an aqueous solution containing such a peptide / protein drug and EDTA is obtained and allowed to stand until the poorly water-soluble composition of the present invention is formed in the solution. Because the production rate of the poorly water-soluble composition of the present invention changes depending on the concentration of the peptide / proteinaceous drug in the aqueous solvent, the concentration of EDTA, and the temperature in the manufacturing process. In this case, 1 ml of calcitonin was added to 1 ml of the aqueous solvent.
In the case of 0 to 5 mg and EDTA 0.5 to 50.0 mg, 2
Time or more, preferably 24 hours to 48 hours, calcitonin 5 mg to 50 mg, EDTA 5.0 to 250 mg, 0.5 hours or more, preferably 6 to 24 hours, calcitonin 50.0 mg or more, saturated solubility, EDTA 250 mg
In the above case, 1 minute or more, preferably 30 minutes to 4 hours can be mentioned. If carried out above room temperature, this standing time will be shorter, and below room temperature a longer time will be preferred.

When the form of the poorly water-soluble composition of the present invention is poorly water-soluble particles, the temperature of the production process is related to the production rate thereof. Therefore, when obtaining poorly water-soluble particles, there is no particular influence on the production of the peptide / protein drug at a stable temperature, but it is preferably 0 ° C to 30 ° C.
It is particularly preferable to carry out the above production method at 4 ° C. to 25 ° C. Further, when obtaining the poorly water-soluble particles of the present invention, it is possible to stir with a stirrer or the like when dissolving the peptide / protein drug and EDTA in an aqueous solvent, and the number of rotations is adjusted during the stirring. By doing so, it is possible to control the particle size of the poorly water-soluble particles produced. As a procedure for dissolving the peptide / proteinaceous drug and EDTA in the aqueous solvent, a method of mixing the peptide / proteinaceous drug dissolved in the aqueous solvent and EDTA dissolved in the aqueous solvent is efficient and preferable. . Thus, a poorly water-soluble composition of the peptide / protein drug of the present invention and the peptide / protein drug comprising EDTA can be obtained. The poorly water-soluble composition of the present invention is used alone or in a conventionally known sustained-release formulation, or by using a poorly water-soluble composition of the present invention and a pharmaceutical preparation comprising a pharmaceutically acceptable carrier, It can be administered intravenously, intraarterially, subcutaneously or intramuscularly or on the skin, and mucous membranes such as the nose, lungs and vagina. Here, the pharmaceutically acceptable carrier is, for example, various liquid bases such as distilled water and the like, such as water absorbability, which are adapted to the shape of the preparation such as liquid preparation and powder preparation according to the administration method described below. -Various bases usually used in powder formulations such as a poorly water-soluble base and / or a water-absorbent / gel-forming base can be mentioned. Then, the poorly water-soluble composition of the present invention and these carriers can be made into the intended pharmaceutical preparation of the present invention by using conventionally known formulation techniques such as dissolution and mixing.

The composition and pharmaceutical preparation of the present invention can be administered by injection, when administered intravenously, intraarterially, subcutaneously or intramuscularly. Peptides and proteins such as lyophilized injections which are soluble before use. Method of administering a general drug to a sexual drug as a general injection, and when administering to mucous membranes of the nose, lungs, vagina, etc., disperse or dissolve in a liquid such as water or a buffer solution, and then use a dispenser for each site such as a spray And a method of administering it as a powder by a freeze-drying method or the like with an administration device to each site.

At this time, in the case of injections, known preservatives, stabilizers, dispersants, pH adjusters, tonicity agents,
Proteolytic enzyme inhibitors and the like may be added. Here, the preservative is used to prevent contamination and decomposition of the preparation by microorganisms, and examples thereof include benzoic acid, benzoic acid esters, benzalkonium chloride, and benzethonium chloride. The stabilizer is used for suppressing chemical decomposition and physical change of the preparation, and examples thereof include L-ascorbic acid and sodium pyrosulfite. The dispersant is used to help disperse the particles uniformly in the liquid, and examples thereof include carboxymethyl cellulose and its sodium salt. Examples of the pH adjusting agent include citrate, acetate, and phosphate as buffering agents for keeping the pH of the solution within a certain range. Further, the isotonicity agent is an isotonicity agent for making the osmotic pressure of the solution equal to that of body fluid, and examples thereof include salt and glucose. In addition, proteolytic enzyme inhibitors are endopeptidases, which are serine protease centers such as trypsin and chymotrypsin, which exist in the living body, and various amino acids, in order to keep peptide / protein drugs more stable in blood and mucous membranes. It is an inhibitor of exopeptidases such as peptidase and carboxypeptidase, and includes aprotinin, gabexate, tranexamic acid and the like.

Further, in the case of a liquid agent to be administered to mucous membranes, known preservatives, stabilizers, dispersants, pH adjusters, tonicity agents, proteolytic enzyme inhibitors and the like may be added, if necessary, like the above-mentioned injections. You may add. In the case of powders for mucous membranes, known lubricants, binders, diluents, coloring agents, preservatives, preservatives, flavoring agents, proteolytic enzyme inhibitors, and water-absorbing / water-insoluble A base, a water-absorbing / gel-forming base and a mixture thereof may be added. Here, the lubricant is for making the powder containing the particles of the present invention uniform, and includes talc, stearic acid and salts thereof, wax and the like. The binder is used to bind the powder containing the particles of the present invention, and examples thereof include starch and dextrin. The diluent is added so that the powder containing the particles of the present invention is administered to a living body in an optimum amount, and examples thereof include starch and lactose. Examples of the coloring agent include Red No. 2 and the like, examples of the preservative include ascorbic acid and the like, examples of the preservative include paraoxybenzoic acid esters and the like, and examples of the flavoring agent include menthol and the like. Examples of proteolytic enzyme inhibitors include aprotinin, gabexate, tranexamic acid, etc. described in the above-mentioned injection. Examples of water-absorbing / water-insoluble bases include crystalline cellulose, crosslinked sodium carboxymethylcellulose, crosslinked starch, gelatin, casein, tragacanth gum, polyvinylpyrrolidone, chitin, chitosan and the like. Further, as a water-absorbent / gel-forming base, hydroxypropyl cellulose,
Hydroxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium polyacrylate, amylose,
Examples include pullulan.

The dose of the poorly water-soluble composition or pharmaceutical preparation of the present invention generally depends on the content of the peptide / protein drug contained in the composition or pharmaceutical preparation and the disease to be applied. It can be appropriately used depending on the type, age / weight of patient, number of administrations, etc.
For example, when calcitonin is used as the peptide / protein drug, the calcitonin content is 0.1 μg.
˜50 mg, preferably 1 μg-10 mg .

The present invention provides a novel, safe, long-term sustained release, and chemically stable pharmaceutical composition or pharmaceutical preparation of a peptide / protein drug,
Its clinical significance is great.

[0021]

EXAMPLES The present invention will be described in detail below with reference to Examples and Reference Examples, but these are for explaining the present invention and do not limit the present invention in any way. [Example 1] Salmon calcitonin / EDTA disodium
Sparingly water-soluble composition of BACHEM CALIFORNIA 100 mg salmon calcitonin and Teikoku Kagaku KK disodium EDTA 75 mg were weighed and dissolved in 10 ml of purified water at room temperature and then left for 1 hour to leave salmon calcitonin-EDTA2. Poorly water-soluble particles of sodium were produced.

[Reference Example 1] The sparingly water-soluble particles of calcitonin / EDTA disodium prepared in Example 1 were freeze-dried, and 5 mg of the dry sparingly water-soluble particles were weighed to obtain 2 m.
It was dispersed in 1 liter of purified water. Then add 2 mg to this dispersion.
When calcium lactate was added, it was visually confirmed that the sparingly water-soluble particles of calcitonin / EDTA disodium were dissolved (the amount of calcium ion to be used to confirm that a chelate was formed and the amount used in this experiment). What is the relationship with?). From this, it is presumed that the poorly water-soluble composition of the present invention has a peptide / protein drug and EDTA chelated.

[Reference Example 2] The sparingly water-soluble particles of calcitonin-EDTA disodium prepared in Example 1 were freeze-dried, and 5 mg of the dry sparingly water-soluble particles were weighed to obtain 2 m.
It was dispersed in 1 liter of purified water. Then add 2 mg to this dispersion.
When Lys was added, it was visually confirmed that the poorly water-soluble particles of calcitonin / EDTA disodium were dissolved (how about this as well). From this, it is presumed that in the poorly water-soluble composition of the present invention, the Lys residue in the peptide / protein drug is chelated with EDTA.

[Test Example 1] Preparation of a salmon calcitonin-containing preparation
Stability BACHEM CALIFORNIA salmon calcitonin 2 mg (control example), salmon calcitonin EDTA disodium pharmaceutical composition obtained by freeze-drying according to Example 4 of JP-A-2-306921 (Comparative Example 1)
And the salmon calcitonin-EDTA2 obtained in Example 1.
Weigh 2.5 mg each of poorly water-soluble sodium particles, put each formulation in a glass vial, and keep at 40 ° C.
It was stored for 1 week in an environment of 75% RH. The residual amount of salmon calcitonin in these preparations was measured by the HPLC method, and the residual ratio (%) from the initial content was calculated. The results are shown in Table 1.

[0025]

[Table 1]

From Table 1, the residual amount of salmon calcitonin in each preparation was 0% for the control (calcitonin drug substance),
Comparative Example 1 (composition described in JP-A-2-306921) was 15%, whereas Example 1 (poorly water-soluble composition of the present invention) was 94%, and salmon calcitonin in the composition of the present invention is very stable. It turns out that

[Test Example 2] Salmon when subcutaneously administered to rabbits
Sustained Release of Cytonin-Containing Preparation A powder obtained by freeze-drying the sparingly water-soluble particles of salmon calcitonin.EDTA disodium prepared in Example 1 was used.
5 mg was weighed and dispersed in 2 ml of physiological saline to obtain a liquid pharmaceutical preparation comprising the poorly water-soluble composition of the present invention and a carrier, and this pharmaceutical preparation was subcutaneously administered to male Japanese white rabbits by 0.2 ml. . Blood was collected from the ear vein at a predetermined time after administration, and the blood concentration (pg / ml) was evaluated by the RIA method.
The results are shown in Table 2.

The salmon calcitonin / EDTA disodium pharmaceutical composition obtained as Comparative Example 1 in Test Example 1 was freeze-dried, and the obtained powder was used to evaluate the blood concentration by the RIA method in the same manner as above. The results are shown in Table 2.

[0029]

[Table 2]

From Table 2, it can be seen that the salmon calcitonin release pattern is completely different between the preparation of Comparative Example 1 and the preparation of Example 1, and that the preparation of the present invention is excellent in the sustained release of salmon calcitonin. I understand. That is, it is clear that the pharmaceutical composition of Comparative Example 1 and the poorly water-soluble composition of the present invention are different compositions.

[Test Example 3] Salmon with oral administration to rabbits
Sustained Release of Cytonin-Containing Formulation 5 mg of powder obtained by freeze-drying the poorly water-soluble particles of calcitonin.EDTA disodium prepared in Example 1 was weighed and dispersed in 2 ml of PBS buffer to obtain a liquid form. The pharmaceutical preparation was administered to male Japanese white rabbits by an oral probe. Blood was collected from the ear vein at a predetermined time after administration, and the blood concentration (pg / ml) was evaluated by the RIA method. Table 3 shows the results
It was shown to.

[0032]

[Table 3]

From Table 3, it can be seen that the poorly water-soluble composition of the present invention remarkably improved the absorption rate of a peptide / protein drug, which was conventionally considered to have an absorption rate of less than 1%, even when it was orally administered. I understand.

[Example 2] CGRP / EDTA2 Natri
Poorly water-soluble composition of um 1 mg of human calcitonin gene-related peptide (CGRP) manufactured by BACHEM CALIFORNIA Co., Ltd. and 0.5 mg of disodium EDTA manufactured by Teikoku Kagaku Co., Ltd. were weighed, and 0.1 ml of purified water in a low temperature room at 4 ° C. CGRP / ED
Slightly water-soluble particles of TA2 sodium were produced.

[Example 3] Somatostatin / EDTA2
Poorly water-soluble composition of sodium Somatostatin 100 mg manufactured by BACHEM CALIFORNIA and 50 mg EDTA disodium sodium manufactured by Teikoku Kagaku Co., Ltd. were weighed and dissolved in 10 ml purified water at room temperature, and then allowed to stand for 2 hours, somatostatin EDTA disodium Of poorly water-soluble particles were produced.

[Test Example 4] Maintaining a preparation containing somatostatin
Sustainable release Somatostatin / sodium EDTA disodium slightly water-soluble particles prepared in Example 3 were freeze-dried to obtain 2 powders.
5 mg was weighed and added to a 500 ml glass beaker containing 200 ml of physiological saline and a magnetic stirrer bar, and a certain amount was sampled at a predetermined time under stirring with a stirrer to measure the amount of somatostatin released from poorly water-soluble particles. Was calculated as the ratio (%) to the dose. The results are shown in Table 4.

[0037]

[Table 4]

From Table 4, it can be seen that the poorly water-soluble composition of the present invention containing somatostatin has an excellent sustained release property.

[Example 4] hGRF / EDTA2 Natri
Poorly water-soluble composition of um 20 mg of human growth hormone releasing factor (hGRF) manufactured by BACHEM CALIFORNIA and Teikoku Kagaku Co., Ltd.
Weigh 5 mg of EDTA disodium and make 1 at room temperature
It was dissolved in 0 ml of purified water, and then left standing for 5 hours to produce sparingly water-soluble particles of hGRF · EDTA disodium.

[Test Example 5] hGR by intranasal administration to rabbits
Sustained Release of F-Containing Formulation 5 mg of powder obtained by freeze-drying poorly water-soluble particles of hGRF · EDTA disodium prepared in Example 4 was weighed. This powder and Asahi Kasei crystalline cellulose 100
By mixing with mg in a mortar, a powdery pharmaceutical preparation comprising the poorly water-soluble composition of the present invention and a carrier was obtained. 10 mg each of the obtained powdered pharmaceutical preparation was injected into the nasal cavity of a male Japanese white rabbit,
It was administered by spraying with a pubizer (registered trademark, Teijin Limited). Blood was collected from the ear vein at a predetermined time after administration, and the blood concentration (pg / ml) was evaluated by the RIA method. Table 5 shows the results.

[0041]

[Table 5]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 38/27 A61K 37/24 38/04 37/26 38/21 37/30 47/18 37 / 32 37/36 37/43 37/66 H (72) Inventor Takao Fujii 4-32 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center

Claims (13)

[Claims] 1. A peptide / protein drug and EDTA
A poorly water-soluble composition of a peptide / protein drug, which comprises: 2. The poorly water-soluble composition is produced by dissolving the peptide / protein drug and the EDTA in an aqueous solvent, and then leaving the obtained aqueous solution until the poorly water-soluble composition is obtained. The sparingly water-soluble composition according to claim 1, which is capable of being treated. 3. The particle is insoluble in water in the form thereof.
Or a poorly water-soluble composition of the peptide / proteinaceous drug according to 2 above. 4. The ED and the peptide / protein drug in an amount of 1.0 mg or more and a saturated solubility or less in 1 ml of the aqueous solvent.
3. TA of 0.5 mg or more is used.
The sparingly water-soluble composition described. 5. The peptide / protein according to any one of claims 1 to 3, wherein the peptide / protein drug has at least one amino acid residue selected from Lys and Arg in its primary structure. Sparingly water-soluble composition of a sex drug. 6. The peptide / protein drug, wherein the number of amino acid residues in its primary structure is 10 to 500.
A poorly water-soluble composition of the peptide / protein drug described in 1. 7. The peptide / protein drug is calcitonin, calcitonin gene-related peptide, somatostatin, growth hormone releasing factor, endothelin,
Endorphins, interleukins, substance Ps, glucagons, glucagon-like peptides, adrenocorticotropic hormones, corticotropin releasing factors, interferons, insulins, growth hormones, growth hormone releasing hormones, erythropoietins, granules 4. The poorly water-soluble peptide / protein drug according to any one of claims 1 to 3, which is one or more peptide / protein drug selected from the group consisting of sphere colony-stimulating factors and macrophage formation-stimulating factors. Composition. 8. The peptide / protein drug is one or more peptide / protein drugs selected from the group consisting of calcitonins, calcitonin gene-related peptides, somatostatins, growth hormone releasing factors, and insulins. A poorly water-soluble composition of the peptide / proteinaceous drug according to any one of claims 1 to 3. 9. A pharmaceutical preparation comprising the poorly water-soluble composition of the peptide / protein drug according to claim 1 and a pharmaceutically acceptable carrier. 10. The pharmaceutical preparation according to claim 9, wherein the preparation form is an injection. 11. The pharmaceutical preparation according to claim 9, wherein the dosage form is a nasal preparation. 12. The pharmaceutical preparation according to claim 9, wherein the preparation form is a transpulmonary drug. 13. The pharmaceutical preparation according to claim 9, wherein the preparation form is an oral preparation.