Sustained release medicinal compositions

Details Sustained release medicinal compositions Sustained release medicinal compositions

2000-06-23

2001-12-11

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

C424S457000, C424S468000, C424S423000

Reexamination Certificate

active

06328979

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a sustained-release pharmaceutical composition for an ionic pharmaceutically active substance (excluding an ionic prostanoic acid derivative). More particularly, the invention relates to a sustained-release pharmaceutical composition comprising an ionic pharmaceutically active substance and an ionic compound which has an opposite charge to that of the ionic pharmaceutically active substance and enhances the hydrophobic property of the ionic pharmaceutically active substance.
RELATED ART
Oral administration has been widely applied to delivery of pharmaceutically active substances. While there is a need for fast-acting drugs, both fast and continuously acting drugs are simultaneously necessary sometimes. In this case, parenteral administration is generally used in combination with oral administration. For parenteral preparations, there are known intravenous, subcutaneous or intramuscular injection; implants and transmucosal preparations through oral cavity, nasal cavity, lung, vagina, rectum, skin, etc. Of these routes, injection is a general choice for administration.
However, sustained release of some medicaments may cause difficulty in parenteral preparations, depending upon the property of a pharmaceutically active substance. For example, such difficulty is noted with pharmaceutically active substances having a short half life in blood, a high water solubility or a low molecular weight. When it is desired to maintain the pharmacological effects of those medicaments over a long period of time, it is the actual practice to administer such a medicament by instillation through the vein or frequently inject the medicament subcutaneously or intramuscularly. A burden of such a treatment is not negligible to patients either physically or mentally. To solve the problem, it has been investigated to create a pharmaceutically active substance having a prolonged half life in blood or to produce a hybrid between a pharmaceutically active substance and a high molecular weight substance such as polyethylene glycol by irreversible bonding of the two substances, thereby to extend the half life of the pharmaceutically active substance itself in blood. Various other techniques for controlling the solubility or dissolution of a pharmaceutically active substance out of a carrier have been studied, which involve insolubilizing or sparingly solubilizing a pharmaceutically active substance in water to delay its dissolution, or microencapsulation of a pharmaceutically active substance using a biodegradable high molecular weight material.
For example, Japanese Patent Application Laid-Open No. 1-163199 discloses that an organic acid with a high molecular weight of about 5,000 or more, e.g., sodium alginate, is added to a cytokine like interleukin 2 so as to reach the isotonic osmotic pressure or more and the mixture is then shaken to form the water-insoluble matter, whereby the insoluble mater is used in a sustained-release composition for injection.
Japanese Patent Application Laid-Open No. 9-208485 discloses a sustained-release preparation comprising a sparingly water-soluble composition formed from a peptide-proteinaceous medicament and EDTA.
Japanese Patent Application Laid-Open Nos. 8-3055 and 8-217691 disclose sustained-release preparations comprising microcapsules obtained by mixing a water-soluble pharmaceutically active substance and a water-soluble polyvalent metal salt, and dispersing the resulting water-insoluble mixture of in a biodegradable high molecular weight material such as polylactic acid-glycolic acid copolymer.
On the other hand, Japanese Patent Application Laid-Open No. 62-129226 discloses that hyaluronic acid or its sodium salt, or Hylan enables a medicament dissolved or dispersed in the solution to achieve continuous release from the solution mainly based on the viscosity of the solution. This publication also discloses that in a cationic group-containing medicament, exchange of ions could occur between this carboxyl group-containing macromolecule of hyaluronic acid and the medicament, where the exchange causes slower diffusion of the medicament out of the system. As a technique utilizing the viscosity of hyaluronic acid, Japanese Patent Application Laid-Open No. 1-287041 discloses a sustained-release preparation suitable for subcutaneous or intramuscular administration, comprising a pharmaceutically active substance and hyaluronic acid or a salt thereof; Japanese Patent Application Laid-Open No. 2-213 also discloses a sustained-release preparation comprising a physiologically active peptide and hyaluronic acid or a salt thereof
However, such a sustained-release preparation utilizing the viscosity of hyaluronic acid provides a fast diffusion of a pharmaceutically active substance from the viscous product, in which the active substance is incorporated. Even taking into account the ionic interaction ability between hyaluronic acid and a cationic medicament coupled to the viscosity of hyaluronic acid, it is suspected that retardation in dissolution is not enough. Yet, any sustained-release parenteral preparation that is satisfactory from a clinical standpoint has been unknown for not only cationic but also ionic pharmaceutically active substances. Particularly in the case of a highly water-soluble ionic pharmaceutically active substance, sustained release could not be attained to a satisfactory extent by the prior art technique of retarding the diffusion using the viscosity of a high molecular weight substance, especially because of its high water solubility.
Japanese Patent Application Laid-Open No. 53-18723 discloses a composition for rectal administration obtained by intimately mixing insulin with a quaternary ammonium salt cationic surfactant. Japanese Patent Application Laid-Open No. 59-89619 discloses a liquid pharmaceutical composition for nasal administration, comprising calcitonin and benzalkonium chloride in a liquid diluent or carrier suitable for application to nasal mucous membrane. However, the techniques described in these gazette publications all aim at improving absorption of a medicament by rectal administration or nasal administration but none of the publications mentions or even suggests sustained release of a medicament involving the imparted hydrophobic property of an ionic complex.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a sustained-release preparation of an ionic pharmaceutically active substance, irrespective of water solubility of the active substance, to such an extent that is satisfactory for clinical use.
Under the foregoing technical level, the present inventors attempted to provide a sustained-release preparation for an anionic pharmaceutically active substance, for which sustained release is required through parenteral route, first by adding an equimolar amount of a cationic compound to the anionic pharmaceutically active substance and forming a sparingly water-soluble ionic complex through ionic interaction between the anionic and cationic compounds, with an expectation to achieve a sustained release. However, subcutaneous administration of the ionic complex formed to rats revealed that no satisfactory sustained-release was obtained. It was thus found that the retarded dissolution of anionic pharmaceutically active substances is insufficient for the purpose of sustained release of ionic pharmaceutically active substances by parenteral route.
In order to further increase the hydrophobicity of the pharmaceutically active substance accompanied by the formation of the ionic complex, the present inventors have brought attention to an octanol/water partition coefficient as an index for the hydrophobicity. As a result, it has been found that depending upon kind of the cationic compound, there is a difference in the partition coefficient of the cationic pharmaceutically active substance associated with the ionic complex formation and that a better sustained release effect is obtained with a larger partition coefficient. It has also been found that the sustained re

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