United States Patent:   6,013,773

Assignee:  Mitsui Chemicals, Inc. (Tokyo, JP)

Filed:  January 31, 1997

A stable pharmaceutical preparation containing a human growth hormone having a molecular weight of about 20,000, or a derivative thereof, can be formulated by adding a water soluble heterocyclic compound, such as creatinine, a salt of acetyltryptophane and nicotinamide, to prevent the insolubilization of the human growth hormone or the derivative thereof in an aqueous solution.

SUMMARY OF THE INVENTION

As described above, it is very difficult to obtain a solution in which 20 k hGH maintains its physiological activity in a soluble and stable form simply, by applying the conventional compounding preparations of 22 k hGH. Accordingly, there is a strong need to develop new compounding prescriptions for stable 20 k hGH pharmaceutical preparations which retain an appropriate concentration for injection.

Furthermore, since lyophilization of 20 k hGH alone cannot prevent the production of related substances and high molecular weight polymer products, there is a need to develop a stable lyophilized pharmaceutical preparations containing 20 k hGH, which produce very little related substances or high molecular weight polymer products.

Accordingly, an object of the present invention is to provide pharmaceutical preparations which contain 20 k hGH and produce very little insoluble matter derived from the 20 k hGH when dissolved in water. Another object of the present invention is to provide lyophilized preparations containing 20 k hGH which suppressed the production of related substances and high molecular weight polymer products after reconstitution.

An additional object of the present invention is to provide methods to prevent the insolubilization of 20 k hGH in a pharmaceutical preparation containing 20 k hGH in order to improve its stability, and a method to suppress the production of related substances and high molecular weight polymer products over time in a lyophilized preparation containing 20 k hGH.

The present inventors did extensive studies to achieve the abovementioned objective, that is, to improve the solubility and stability of 20 k hGH and to provide a compounding prescription for a stable 20 k hGH preparation upon lyophilization. As a result, the present inventors have succeeded in producing a pharmaceutical preparation containing 20 k hGH which has excellent solubility and stability.

Furthermore, the present inventors found that when a basic amino acid and a nonionic surfactant are added to a lyophilized preparation containing 20 k hGH, the production of related substances of the lyophilized preparation was suppressed to improve stability, such that said lyophilized preparation did not produce any insoluble matter when reconstituted in water; thereby completing the present invention.

Namely, the present invention comprises pharmaceutical preparations containing a human growth hormone having a molecular weight of about 20,000, or a derivative thereof, and a water soluble heterocyclic compound; methods to prevent insolubilization of a human growth hormone having a molecular weight of about 20,000, or a derivative thereof, thereby improving the stability of a pharmaceutical preparation containing said human growth hormone or a derivative thereof by adding a water soluble heterocyclic compound; and methods to suppress the production of related substances over time in a lyophilized preparation containing a human growth hormone having a molecular weight of about 20,000, or a derivative thereof, by adding one or two kinds of basic amino acids, or salts thereof, and a nonionic surfactant.

The present inventors found that the solubility of 20 k hGH can be improved by adding a water soluble heterocyclic compound, such as creatinine, in a certain concentration to a 20 k hGH preparation in which the use of buffer solutions generally used for physiological substances would not provide a sufficient concentration of 20 k hGH for use as a pharmaceutical preparation.

Furthermore, it is possible to prevent the production of extremely small amounts of insoluble matter by controlling the pH of an aqueous 20 k hGH. It was also found that the stability in solution upon thawing can be improved by adding a nonionic surfactant such as polysorbate 80, and furthermore, stability upon lyophylized preparation and during reconstitution can be improved by adding basic amino acids and mannitol, a sugar alcohol. These findings readily enable the mass production of pharmaceutical preparations containing lyophilized 20 k hGH which can be reconstitution to prepare aqueous solutions suitable for injection.

Claim 1 of 62 Claims

1. A stable pharmaceutical preparation which comprises an aqueous solution containing a pharmaceutically effective amount of a human growth hormone having a molecular weight of about 20,000, and further comprising an amount of at least one compound selected from the group consisting of creatinine, an acetyl tryptophan salt, and nicotinamide, sufficient to enhance the solubility of said human growth hormone.

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