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Liquid Preparation of Physiologically Active Peptide

Inactive Publication Date: 2008-08-14
ASUBIO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0062]According to the present invention, there is provided an effective liquid preparation that achieves high bioavailability (BA) of physiologically active peptides or proteins, including ghrelins, these are administered as drugs.
[0063]There is also provided a method for improving the BA of physiologically active peptides or proteins, including ghrelins, these are subcutaneously injected in aqueous solutions.
[0064]Thus, the present invention makes it possible to maintain the blood level of physiologically active peptides or proteins, including ghrelins, that are subcutaneously injected: To date, it has been considered difficult to maintain therapeutically effective plasma levels of subcutaneously injected peptides and proteins. The present invention therefore is of significant medical importance.

Problems solved by technology

Continuous, long-term treatment of diseases by injection requires patients to visit a hospital or clinic to receive treatment and poses a significant burden to patients.
Drugs administered by subcutaneous injection, however, are decomposed by proteases during the subcutaneous absorption process and their bioavailability generally becomes lower than is achieved by intravenous injection.
Thus, subcutaneous injections still remain stressful to patients.
Despite high expectations for application of ghrelins comprising ghrelin, ghrelin derivatives and ghrelin analogues in pharmaceutical products, no viable pharmaceutical compositions have yet to be designed and much still remains unknown about the pharmacokinetics of the compounds.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Preparations Containing Human Ghrelin (2)

[0107]The following buffers were prepared as described below: 0.5M sodium acetate buffer, 0.5M ammonium acetate buffer, 0.5M acetic acid buffer, 0.5M sodium phosphate buffer, 0.5M citric acid buffer, 0.5M glycine hydrochloride buffer, 1M lactic acid buffer, 0.06M propionic acid buffer and 0.06M n-butyric acid buffer. The pH of each buffer is shown in the parenthesis.

(1) 0.5M Sodium Acetate Buffer (pH 7.0)

[0108]Purified water was added to 8.20 g sodium acetate (MW=82.03) to a volume of 100 mL. To this solution, 1M hydrochloric acid was added to a pH of 7.0. Purified water was further added to a final volume of 200 mL.

(2) 0.5M Sodium Acetate Buffer (pH 4.0)

[0109]Purified water was added to 8.20 g sodium acetate (MW=82.03) to a volume of 100 mL. To this solution, 1M hydrochloric acid was added to a pH of 4.0. Purified water was further added to a final volume of 200 mL.

(3) 0.5M Sodium Acetate Buffer (pH 5.0)

[0110]Purified water wa...

example 2

Effects of Sodium Acetate Buffers on Pharmacokinetics of Subcutaneously Injected Ghrelin in Rats

[0132]As in Comparative Example 2, Preparations No. 34, No. 6 and No. 7 were subcutaneously administered at a dose of 1 mL / kg and the plasma ghrelin levels were measured by RIA method. The results are shown in FIG. 2. The pharmacokinetic parameters are shown in Table 7 below.

Table 7: Pharmacokinetic Parameters of Ghrelin Preparations Subcutaneously Administered to Rats (Effects of Sodium Acetate Buffer)

[0133]

TABLE 7Dose volumeCmaxTmaxAUCBAPrepar. No.(mL / kg)(ng / mL)(min)(ng · min / mL)(%)341 3.35 ± 1.285.00 ± 0.00 51.94 ± 21.60 5.0 ± 2.16112.57 ± 1.625.00 ± 0.00235.38 ± 22.5922.9 ± 2.27122.29 ± 8.978.33 ± 2.89363.38 ± 16.6435.3 ± 1.6

[0134]As can be seen from the results of Table 7, the BAs obtained for Preparations No. 6 and No. 7 were 22.9% and 35.3%, respectively. These were surprisingly high as compared to the BA for Preparation No. 34 with physiological saline (5.0%) and the BA for Prepar...

example 3

Effects of the Type of Acid Solution on Pharmacokinetics of Subcutaneously Injected Ghrelin in Rats

[0135]As in Comparative Example 2, Preparations No. 7, No. 8, No. 9, No. 10 and No. 11 were subcutaneously administered at a dose of 1 mL / kg and the plasma ghrelin levels were measured by RIA method. The pharmacokinetic parameters are shown in Table 8 below.

Table 8: Pharmacokinetic Parameters of Ghrelin Preparations Subcutaneously Administered to Rats (Effects of Types of Acid Solution)

[0136]

TABLE 8Dose volumeCmaxTmaxAUCBAPrepar. No.(mL / kg)(ng / mL)(min)(ng · min / mL)(%)7122.29 ± 8.978.33 ± 2.89363.38 ± 16.6435.3 ± 1.68113.29 ± 4.746.67 ± 2.89214.93 ± 41.0120.9 ± 4.091 3.70 ± 1.0913.33 ± 5.77  72.02 ± 10.33 7.0 ± 1.0101 6.12 ± 3.606.67 ± 2.89 91.68 ± 76.60 8.9 ± 7.411110.99 ± 5.405.00 ± 0.00167.50 ± 61.1116.3 ± 5.9

[0137]The BAs obtained for Preparations No. 7, No. 8, No. 9, No. 10 and No. 11 were 35.3%, 20.9%, 7.0%, 8.9% and 16.3%, respectively. Thus, the BA of ghrelin was markedly increa...

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Abstract

An effective liquid preparation achieves high bioavailability (BA) of physiologically active peptides or proteins, including ghrelins, that are administered as drugs. Also provided is a method for improving the BA of physiologically active peptides or proteins, including ghrelins, that are subcutaneously injected in aqueous solutions. The liquid preparation contains: a physiologically active peptide or protein, such as ghrelins, as an active ingredient; an acid solution including one or a combination of two or more selected form the group consisting of acetic acid, lactic acid, phosphoric acid, glycine, citric acid, hydrochloric acid, propionic acid, butyric acid, benzoic acid and salts thereof; an alcohol; and a polar organic liquid including one or a combination of two or more selected from the group consisting of N-methyl-2-pyrrolidone, dimethylformamide, dimethylsulfoxide and methylparaben.

Description

TECHNICAL FIELD[0001]The present invention relates to a liquid preparation of a physiologically active peptide or a physiologically active protein with improved bioavailability, as well as to a method for improving the bioavailability of a physiologically active peptide or a physiologically active protein.BACKGROUND ART[0002]Pharmaceutical preparations of a variety of physiologically active peptides or physiologically proteins are currently available in the market place. Among such physiologically active peptides or physiologically proteins are insulin, growth hormones, atrial natriuretic peptide, calcitonin, LHRH analogues, parathyroid hormone, and adrenocorticotropic hormone derivatives. Since these compounds are deactivated in the gastrointestinal tract by the action of proteases, they are rarely administered in oral preparations; most are formulated as parenteral preparations such as injections for clinical use.[0003]Continuous, long-term treatment of diseases by injection requi...

Claims

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Application Information

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IPC IPC(8): C12N9/94
CPCA61K9/0019A61K38/25A61K47/10A61K47/40A61K47/22A61K47/26A61K47/12A61P13/10A61P3/10A61P5/00A61P5/06A61P5/10A61P5/14A61K9/08A61K38/04A61K47/14
Inventor MATSUMOTO, MASARUMATSUMOTO, MASAKOHANADA, TAKESHIWAKABAYASHI, NAOMI
Owner ASUBIO PHARMA
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