JP2002193830A - Medicinal preparation for nasal administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicinal preparation which contains a medicinally active polypeptide and is used for nasal administration. SOLUTION: This medicinal preparation for nasal administration comprises (1) a medicinally active polypeptide, (2) one or more compounds selected from the group consisting of taurine, its 1 to 6C ester and its basic metal salt and hyaluronic acid and its basic metal salt, and (3) one or more pharmacologically acceptable additives. Since the medicinally active polypeptide-containing medicinal preparation for the nasal administration exhibits a good medicinal activity and does not have observable irritation and other observable bad effects to nasal mucosa, the medicinal preparation is a preparation suitable for administration through the nasal mucosa.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical preparation for nasal administration containing a pharmaceutically active polypeptide. More specifically, the present invention relates to the use of taurine, its C
_{The present invention} relates to a pharmaceutical preparation for nasal administration containing one or more compounds selected from the group consisting of _1-6 esters and base metal salts thereof and hyaluronic acid and base metal salts thereof. The pharmaceutical preparation for nasal administration of the present invention is administered via the nasal mucosa.

[0002]

2. Description of the Related Art A powdery composition for intranasal administration containing a physiologically active peptide comprising butylene glycol hyaluronate as a carrier is known (JP-A-6-199681).
No.). A pharmaceutical composition for transmucosal administration, which contains a peptide hormone and hyaluronic acid (salt) and preferably has a pH of about 4, is known (JP-A-3-246233). Microspheres in which a physiologically active peptide is surrounded by or adsorbed by a hyaluronic acid ester are known (JP-A-7-179363). Pharmaceutical preparations comprising a physiologically active peptide, hyaluronic acid or a non-toxic salt thereof, and a polymer substance and having improved drug release properties are known (JP-A-5-97694).
A transpulmonary preparation comprising a peptide drug and hyaluronic acid is known (JP-A-9-309843). A physiologically active preparation containing hyaluronic acid or a non-toxic salt thereof is known (JP-A-2-213). Nasal powder preparations containing granulocyte colony stimulating factor, saccharides and hyaluronic acid or a salt thereof are known (JP-A-8-1987).
No. 72). Eye drops containing insulin and hyaluronic acid or a salt thereof as a thickener are known (JP-A-1-294633). A long-lasting water-soluble pharmaceutical composition containing a pharmaceutically active peptide, water-soluble hyaluronic acid and a water-soluble protein having no pharmacological activity is known (JP-A-5-186362). A bioactive peptide composition in which a bioactive peptide is uniformly dispersed and adhered to hyaluronic acid as a carrier is known (Japanese Patent Application Laid-Open No.
-118170). A highly absorptive transvaginal agent containing taurine as an absorption promoter in a biologically active polypeptide is known (JP-A-3-99021). Chinese Patent Application No. 951199260.4 discloses an accelerator of the mucosal absorption type of a polypeptide drug. Examples of such an accelerator include azone, saponin, glycyrrhizinoic acid and its esters and salts, glycyretinic acid and its sodium salt, dihydroxymolinetannic acid and its derivatives, carboxylic acid esters, and the like. However, the only example in that application is a sublingual tablet. Chinese Patent Application No. 881066763.6 discloses a pharmaceutical formulation for administration via the mucosa. The absorption enhancer contained in the preparation is D-erythrose, D-ribose, D-ribulose, D-xylose, D-arabinose, D-mannose, resorbose, D-sedumeptulo.
and monosaccharides such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and side-chain cyclodextrin.

[0003]

SUMMARY OF THE INVENTION Polypeptide compounds are easily degraded by enzymes in the gastrointestinal tract, are easily metabolized in the liver, and are unlikely to exert their original pharmacological effects in the body of patients. Therefore, the polypeptide compound is usually used in the form of an injection such as subcutaneous injection, intramuscular injection, intravenous injection, and the like. However, for patients, receiving long-term injections of polypeptides can result in muscle tissue damage,
It can be painful and irritating, such as necrosis, and can transfer infectious and other diseases by injection. In addition, various inconveniences such as going to hospital will also occur. For these reasons, it has recently been noted that polypeptide compounds are administered through mucous membranes such as the nasal mucosa, but polypeptide pharmaceutical preparations for administration via the nasal mucosa are not commercially available. Accordingly, there is a high demand for polypeptide pharmaceutical preparations for administration through the nasal mucosa, and their development is urgent. An object of the present invention is to provide a pharmaceutical preparation for nasal administration containing a pharmaceutically active polypeptide.

[0004]

Means for Solving the Problems The present inventor has conducted intensive studies to solve the above-mentioned problems, and as a result, it has been found that a drug containing a pharmaceutically active polypeptide having a drug activity equivalent to that of injection administration and having no irritation. A pharmaceutical preparation for nasal administration was found, and the present invention was completed. The pharmaceutical preparation for nasal administration of the present invention comprises (1)
A pharmaceutically active polypeptide, (2) one or more compounds selected from the group consisting of taurine, its C _1-6 ester and its base metal salt, and hyaluronic acid and its base metal salt, and (3) a pharmacologically acceptable It contains one or more of the resulting additives. Preferred pharmaceutical preparations for nasal administration of the present invention are (1) a pharmaceutically active polypeptide, (2) one or more compounds selected from taurine, its C _1-6 ester and its base metal salt,
(3) 1 selected from hyaluronic acid and its base metal salt
It contains one or more of the above compounds and (4) pharmacologically acceptable additives. Further, the preferred pharmaceutical preparation for nasal administration of the present invention comprises (1) a pharmaceutically active polypeptide, (2) one or more compounds selected from taurine, its C _1-6 ester and its base metal salt, and (3) Contains one or more pharmacologically acceptable additives. In the present invention, taurine,
1 selected from the C _1-6 ester and its base metal salt
The above compounds and one or more compounds selected from hyaluronic acid and base metal salts thereof act as an absorption activator of the pharmaceutically active polypeptide.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, pharmaceutically active polypeptides include, for example, insulin obtained from bovine and porcine or artificially synthesized insulin, calcitonin, hirudin, glucacogen, angiotensin, lactating hormone, growth hormone, thyroid stimulating hormone. (TSH), adrenocorticotropins and polypeptides such as interferons. One preferred embodiment of the pharmaceutical preparation for nasal administration of the present invention relates to a pharmaceutical preparation for treating diabetes by administration via the nasal mucosa, which contains insulin as the above-mentioned pharmaceutically active polypeptide.

The base metal salt of taurine, which is one of the absorption enhancers of the pharmaceutical preparation for nasal administration of the present invention, includes the sodium salt and potassium salt of taurine. The base metal salt of hyaluronic acid, which is one of the absorption promoters, includes sodium and potassium salts of hyaluronic acid. Insulin, one of the pharmaceutically active polypeptides that is a preferred active ingredient of the pharmaceutical preparation for nasal administration of the present invention, is produced by natural insulin obtained from animals (eg, cows and pigs), synthetic insulin, and recombinant DNA technology. Containing recombinant insulin.

[0007] Diabetes to be treated with the pharmaceutical preparation for nasal administration of the present invention containing the above-mentioned insulin and the like include type I diabetes and type II diabetes. The pharmaceutical preparation for nasal administration of the present invention is used in the form of a liquid drop or spray. Pharmaceutical formulations for nasal administration of the invention in the form of liquid drops or sprays are administered to humans, for example, via the nasal mucosa.

The pharmaceutical preparation for nasal administration containing the pharmaceutically active polypeptide of the present invention comprises 0.01 to 20 w / v% of taurine or a base metal salt thereof or a C _1-6 alkyl ester or 0.01 to 10 w / v%. / V% of hyaluronic acid or a base metal salt thereof, or a mixture thereof as an absorption promoter. The pH of an aqueous solution or a pharmaceutical preparation for nasal administration containing the pharmaceutically active polypeptide of the present invention is usually 6
-8, preferably 6.5 to 7.5.

A pharmaceutical preparation for nasal administration containing the pharmaceutically active polypeptide of the present invention is produced, for example, as follows. One or more compounds selected from the group consisting of taurine, its C _1-6 ester and its base metal salt and hyaluronic acid and its base metal salt, optionally a preservative N
An appropriate amount of distilled water is added to an additive such as ipagin A (ethyl p-hydroxybenzoate), and the mixture is heated to dissolve the compound.
H is preferably adjusted to 6.5 to 7.5, more preferably about 7.0, and then a pharmaceutically active polypeptide such as insulin is added. A pharmaceutically active polypeptide is added. After dissolving the pharmaceutically active polypeptide, the filtrate obtained by sterile filtration is packed in a syringe bottle having a specific property.

The dose of the pharmaceutical preparation for nasal administration containing a pharmaceutically active polypeptide which is administered via the nasal mucosa of the present invention depends on the age, body weight, physical condition and disease symptoms of the patient, It depends on the presence or absence, its type, the type of pharmaceutically active polypeptide, and the like. Usually, the dose of the pharmaceutical preparation for nasal administration containing a pharmaceutically active polypeptide of the present invention is determined according to the known dose of the pharmaceutically active polypeptide.

[0011]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples unless it exceeds the gist of the invention. [Example 1] Production of a pharmaceutical preparation for nasal administration Formulation: Ingredients Insulin 20000 IU Taurine 2 g 0.1 N hydrochloric acid or 0.1 N sodium hydroxide Proper amount Nipagin A (ethyl p-hydroxybenzoate) 0.03 g Add up to 100 ml distilled water

An appropriate amount of distilled water is added to the above-mentioned taurine and Nipagin A, and the mixture is dissolved by heating, and then, using 0.1N hydrochloric acid or 0.1N sodium hydroxide, pH = 7.
And add the above insulin. After dissolution, sterile filtration is performed, and the obtained filtrate is packed in a specially prepared sterile syringe bottle.

Example 2 Ingredients for Pharmaceutical Preparation for Nasal Administration Amount Insulin 20000 IU Hyaluronic acid 0.5 g 0.1 N hydrochloric acid or 0.1 N sodium hydroxide Suitable amount Nipagin A (ethyl p-hydroxybenzoate) 0.03 g Distilled water 100 ml Add up to

An appropriate amount of distilled water is added to the above-mentioned hyaluronic acid and Nipagin A, and the mixture is dissolved by heating. Then, the pH is adjusted to 7 using 0.1N hydrochloric acid or 0.1N sodium hydroxide. Add. After dissolution, sterile filtration is performed, and the obtained filtrate is packed in a specially prepared sterile syringe bottle.

Example 3 Ingredients for Pharmaceutical Preparation for Nasal Administration Amount Insulin 20000 IU Taurine 2 g Hyaluronic acid 1 g 0.1 N hydrochloric acid or 0.1 N sodium hydroxide Suitable amount Nipagin A (ethyl p-hydroxybenzoate) 0.03 g distilled water Add up to 100ml

After adding an appropriate amount of distilled water to the above taurine and hyaluronic acid, heating and dissolving, the pH is adjusted to 7 using 0.1N hydrochloric acid or 0.1N sodium hydroxide, and the above insulin is adjusted. Add. After dissolution, sterile filtration is performed, and the obtained filtrate is packed in a specially prepared sterile syringe bottle.

[Example 4] Comparison of the effect of blood glucose level on alloxan diabetes in large rats caused by injection of alloxan using the insulin-containing pharmaceutical preparation for nasal administration of the present invention in the form of nasal drops. Experimented. Materials Animals: Wistar large mice, male, weight 200-22
0g, purchased from the Chinese Military Medical Science Animal Center. Pass Certificate Number: Kyodo Kanji (1994) No. 052. Insulin-containing pharmaceutical preparation of the present invention; used amounts are 10 IU insulin / kg, 5 IU insulin / kg and 2.
5 IU insulin / kg.

Reagents and Equipment Alloxan: Lot No. FL0612002115
3, Commercial product, made in Hong Kong. Ultraviolet-visible spectrophotometer: made in Japan Experimental method: The above healthy rats are selected, fasted for 24 hours (free to drink water), and then intravenously injected with a salt solution of alloxan 40 mg / kg. The animals are fasted again (freely drink water) 36 hours after the injection and the experiment is started 12 hours after the injection. At the start of the experiment, 30 per mouse
After injecting mg / kg sodium pentobarbital anesthetic into the abdomen, blood is collected and the blood glucose level is measured. The experiment is divided into a blank control group, a model group and a dose group. The blank control group is a group not injected with alloxan, and the experimental pharmaceutical preparation of the present invention containing no insulin is dropped into the nostril for the blank control group and the model group. 1 drop
0 μl / 100 g. 1 for the medication group
0 IU insulin / kg, 5 IU insulin / kg
The same amount (10 μl / 100 g) of the pharmaceutical preparation for experimental nasal administration as in the above two sets of the present invention, containing 2.5 IU insulin / kg, is dropped into the nostrils. Dosing one,
Two, three and four hours later, blood is collected from each set of rats, and blood glucose levels are measured and compared. Table 1 shows the results.

[0019]

[Table 1]

The data in Table 1 show that the insulin-containing pharmaceutical preparation of the present invention is absorbed by the nasal mucosa and has an effective hypoglycemic effect.

[0021]

The pharmaceutical preparation for nasal administration containing a pharmaceutically active polypeptide of the present invention shows good drug activity, and no irritating or other adverse effects on the nasal mucosa are observed. Therefore, the pharmaceutical preparation of the present invention is a very excellent pharmaceutical preparation for administration via the nasal mucosal system.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA12 AA25 BB25 CC30 DD23Z DD30Z DD44R DD55N EE37N FF34 FF68 4C084 AA03 BA44 CA21 CA59 DA21 DB01 DB21 DB22 DB23 DB24 DB31 DB34 DB35 DC35 DC50 MA05 MA13 MA17 MA59 NA10 NA11 Z

Claims (33)

[Claims] (1) one or more compounds selected from the group consisting of (1) a pharmaceutically active polypeptide, (2) taurine, its C _1-6 ester and its base metal salt, and hyaluronic acid and its base metal salt; A) a pharmaceutical formulation for nasal administration comprising one or more pharmacologically acceptable additives. 2. A compound selected from the group consisting of (1) a pharmaceutically active polypeptide, (2) one or more compounds selected from taurine, a C _1-6 ester thereof and a base metal salt thereof, and (3) a hyaluronic acid and a base metal salt thereof. The pharmaceutical preparation for nasal administration according to claim 1, comprising one or more compounds and (4) one or more pharmacologically acceptable additives. 3. A pharmaceutically active polypeptide, (2) one or more compounds selected from taurine, its C _1-6 ester and its base metal salt, and (3) a pharmacologically acceptable additive. The pharmaceutical preparation for nasal administration according to claim 1, which comprises one or more of the following. 4. The method of claim 1, wherein the pharmaceutically active polypeptide is insulin,
The pharmaceutical preparation for nasal administration according to claim 1, 2 or 3, which is selected from the group consisting of calcitonin, hirudin, glucagon, angiotensin, lactating hormone, growth hormone, thyroid stimulating hormone, adrenocorticotropin and interferon. 5. The pharmaceutical preparation for nasal administration according to claim 4, wherein the pharmaceutically active polypeptide is insulin. 6. The method according to claim 1, which is a drop or a spray.
4. The pharmaceutical preparation for nasal administration according to 2 or 3. 7. 0.01~20w / v% of taurine, the C _1-6 ester and nasal administration medicament according to claim 1 comprising one or more compounds selected from the group consisting of the nucleotide metal salts Formulation. 8. The pharmaceutical preparation for nasal administration according to claim 1, comprising 0.01 to 10 w / v% of one or more compounds selected from hyaluronic acid and base metal salts thereof. 9. At least one compound selected from the group consisting of 0.01 to 20% w / v% taurine, its C _1-6 ester and its base metal salt, and 0.01 to 10% w / v% of hyaluronic acid and its base metal. The pharmaceutical preparation for nasal administration according to claim 2, comprising one or more compounds selected from salts. 10. The pharmaceutical preparation for nasal administration according to claim 1, wherein the base metal salt is a sodium salt or a potassium salt. 11. The pharmaceutical preparation for nasal administration according to claim 1, wherein the additive is an excipient. 12. The method according to claim 1, wherein the excipient is water.
2. The pharmaceutical preparation for nasal administration according to item 1. 13. The pharmaceutical preparation for nasal administration according to claim 1, wherein the additive is a preservative. 14. The pharmaceutical preparation for nasal administration according to claim 13, wherein the preservative is ethyl p-hydroxybenzoate. 15. The pharmaceutical preparation for nasal administration according to claim 1, wherein the pH is in the range of 6 to 8. 16. The pharmaceutical preparation for nasal administration according to claim 15, wherein the pH is in the range of 6.5 to 7.5. 17. One or more compounds selected from the group consisting of (1) insulin, (2) taurine which is an absorption enhancer, its C _1-6 ester and its base metal salt, and hyaluronic acid and its base metal salt. The pharmaceutical preparation for nasal administration according to claim 1, which is a pharmaceutical preparation for treating diabetes, which comprises one or more of (3) a pharmacologically acceptable additive. 18. (1) insulin, (2) one or more compounds selected from taurine, its C _1-6 ester and its base metal salt, which is an absorption enhancer, (3) hyaluronic acid and its base metal salt The pharmaceutical preparation for nasal administration according to claim 17, which is a pharmaceutical preparation for treating diabetes, comprising a mixture of one or more compounds selected from the group consisting of: and (4) one or more pharmacologically acceptable additives. 19. One or more of (1) insulin, (2) one or more compounds selected from taurine, its C _1-6 ester and its base metal salt, and (3) one or more pharmacologically acceptable additives. The pharmaceutical preparation for nasal administration according to claim 17, comprising: 20. The method according to claim 1, which is a drop or a spray.
20. The pharmaceutical preparation for nasal administration according to 7, 18 or 19. 21. The pharmaceutical preparation for nasal administration according to claim 17, 18 or 19, wherein the insulin is porcine or synthetic insulin. 22. The pharmaceutical preparation for nasal administration according to claim 17, 18 or 19, wherein the diabetes is type I or type II diabetes. 23. Taurine at 0.01-20% w / v,
1 selected from the C _1-6 ester and its base metal salt
The pharmaceutical preparation for nasal administration according to claim 17 or 19, comprising the above compound. 24. The pharmaceutical preparation for nasal administration according to claim 17, which comprises 0.01 to 10 w / v% of one or more compounds selected from hyaluronic acid and a base metal salt thereof. 25. Taurine at 0.01-20% w / v,
1 selected from the C _1-6 ester and its base metal salt
19. The pharmaceutical preparation for nasal administration according to claim 18, comprising the above compound and one or more compounds selected from hyaluronic acid and a base metal salt thereof at 0.01 to 10 w / v%. 26. The base metal salt is a sodium salt or a potassium salt.
26. The pharmaceutical preparation for nasal administration according to any one of 4 and 25. 27. The method according to claim 17, wherein the additive is an excipient.
20. The pharmaceutical preparation for nasal administration according to 8 or 19. 28. The pharmaceutical preparation for nasal administration according to claim 17, wherein the excipient is water. 29. The method according to claim 17, wherein the additive is a preservative.
20. The pharmaceutical preparation for nasal administration according to 8 or 19. 30. The pharmaceutical preparation for nasal administration according to claim 29, wherein the preservative is ethyl p-hydroxybenzoate. 31. The administration according to claim 1, which is administered via the nasal mucosa.
30. The pharmaceutical preparation for nasal administration according to any one of 30. 32. The method according to claim 1, wherein the pH is in the range of 6 to 8.
20. The pharmaceutical preparation for nasal administration according to 7, 18 or 19. 33. The pharmaceutical preparation for nasal administration according to claim 32, wherein the pH is in the range of 6.5 to 7.5.