Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1999-08-18
2003-03-25
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S450000, C424S455000, C424S489000, C424S502000, C514S937000, C514S938000, C514S943000
Reexamination Certificate
active
06537561
ABSTRACT:
TECHNICAL FIELD
The invention relates to a drug-containing o/w type fat emulsion for oral administration.
BACKGROUND ART
In order that the drug administered orally may be absorbed from the gastrointestinal tract, it is generally necessary that the drug be dissolved within the digestive tract in advance. Therefore, when the drug is a so-called lipophilic drug which is sparingly soluble in the digestive tract, improvements in its gastrointestinal absorption are generally sought by increasing its intra-gastrointestinal solubility through a variety of techniques such as salt formation, modification of crystal form, comminution, and use of a surfactant.
It may also be regarded as one of such pharmaceutical techniques to entrap a drug in fat emulsion particles and administer the resulting fat emulsion. Entrapping a drug in fat emulsion particles stabilizes the drug and improves its dispersibility in the digestive tract, with the result that increases in absorption area and solubility can be expected.
A fat emulsion comprising fat emulsion particles having an average particle diameter of not greater than 200 nm is also known (e.g. Tokkyo Kokai Koho H2-203) and it is generally considered that this emulsion can be administered orally and parenterally. There also is some literature describing pharmaceutical products for oral administration which are based on fat emulsions of relatively large particle size (e.g. Tokkyo Kokai Koho S61-56122).
However, it is suspected that when the conventional fat emulsion is administered orally, the emulsion particles of the fat emulsion are, destroyed by the enzymes in the digestive tract so that the components of the fat emulsion particle are absorbed independently of one another into the absorbing cells, with the result that even when a drug is administered orally in the form of a fat emulsion, the pharmacokinetics of the drug contained in the fat emulsion particles do not agree with the pharmacokinetics of the fat emulsion particles as such which apply to direct administration into the blood vessel. Therefore, when the conventional fat emulsion is administered orally, it seems difficult to achieve the expected effect in terms of absorption, avoidance of metabolism, and transfer to the target tissue.
In addition, the fat emulsion particles of the conventional fat emulsion are destroyed in the digestive tract, it seems difficult to find a correlation between the particle diameter of the particles constituting the fat emulsion and the bioavailability or blood concentration of the drug after oral administration or avoid recognition by the p-glycoprotein (discharging pump) in the absorbing cells of the digestive tract.
DISCLOSURE OF THE INVENTION
The invention has for its object to provide a medical o/w type fat emulsion for oral medication which insures a high bioavailability or blood concentration of a drug.
After intensive research the inventors of the invention found a medical o/w type fat emulsion capable of accomplishing the above object and have developed the invention.
The invention relates to an o/w fat emulsion in which fat emulsion particles composed essentially of an oil component, an emulsifier, and a drug are dispersed in water, characterized in that the average particle diameter of the fat emulsion particles is within the range of 5-50 nm, or a freeze-dried version of said emulsion. The invention further relates to an o/w fat emulsion for oral administration in which fat emulsion particles composed essentially of an oil component, a phospholipid, bile acid or a salt of bile acid, and a drug are dispersed in water, characterized in the average particle diameter of said fat emulsion particles lies within the range of 5-50 nm. By the use of a phospholipid and bile acid or a salt of bile acid in combination, the absorption of the drug from the gastrointestinal tract may be further enhanced.
The invention is now described in detail.
The oil component for use in the invention is not particularly restricted provided that it is an oil component which can be used in pharmaceutical products, thus including vegetable oil, animal oil, neutral lipid (mono-substituted, di-substituted or tri-substituted glyceride), synthetic oil or fat, and sterol derivatives. More particularly, the vegetable oil includes but is not limited to soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil and safflower oil; the animal oil includes but is not limited to fish oil; the neutal lipid includes but is not limited to triolein, trilinolein, tripalmitin, tristearin, trimyristin and triarachidonin; the synthetic lipid includes but is not limited to azone; and the sterol derivatives include but are not limited to cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate and cholesteryl arachidate. Optionally, more than one of those substances may be employed in combination. The preferred oil component includes triglycerides and vegetable oils composed predominantly thereof. Soybean oil is preferred for practical purposes and, in particular, soybean oil purified to a high purity grade is preferred.
The oil component content of the fat emulsion for oral administration according to the invention (hereinafter referred to as “the emulsion of the invention”) should vary according to species of the oil component used and other components but may judiciously be somewhere within the range of 0.1-30 w/v %, preferably 1-20 w/v %. The same range applies as well to the invention wherein bile acid or a salt of bile acid is one of the essential components of the fat emulsion particle.
The emulsifier for use in the invention is not particularly restricted provided that it can be used in pharmaceutical products, thus including phospholipids and nonionic surfactants. More particularly, the phospholipid includes but is not limited to phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, sphingomyelin and lecithin. Hydrogenated phospholipids can also be used. The nonionic surfactant includes but is not limited to polyalkylene glycols (e.g. a polyethylene glycol with an average molecular weight of 1000-10000, preferably 4000-6000), polyoxyalkylene copolymers (e.g. a polyoxyethylene-polyoxypropylene copolymer with an average molecular weight of 1000-20000, preferably 6000-10000), hydrogenated castor oil-polyoxyalkylene derivatives (e.g. hydrogenated castor oil-polyoxyethylene(20)-ether, (40)-ether, and (100)-ether), and castor oil-polyoxyalkylene derivatives (e.g. castor oil-polyoxyethylene (20)-ether, (40)-ether, and (100)-ether). Those may be used in a combination of two or more different species. As the preferred emulsifier, egg yolk phosphatidylcholine, egg yolk lecithin and soybean lecithin can be mentioned. For practical purposes, egg yolk lecithin and soybean lecithin are preferred. As the phospholipid for use in the invention wherein bile acid or a salt of bile acid is used as an essential component, too, egg yolk phosphatidylcholine, egg yolk lecithin and soybean lecithin are preferred.
The emulsifier content of the emulsion of the invention varies with different species of the emulsifier and other components but may judiciously be somewhere within the range of 0.05-40 w/v %, preferably 0.1-20 w/v %. The same range applies as well to the phospholipid for use in the invention wherein bile acid or a salt of bile acid is used as one of the essential components.
The bile acid or the salt of bile acid, which can be used in the invention, includes but is not limited to taurocholic acid, sodium taurocholate, glycocholic acid, sodium glycocholate, sodium taurodeoxycholate, deoxycholic acid and sodium deoxycholate. Those compounds can be used in a combination of two or more species. As the preferred bile acid or salt of bile acid, taurocholic acid and sodium taurocholate can be mentioned. Particularly when the phospholipid is lecithin, the concominant use of sodium taurocholate as said bile acid or salt of bile acid is preferred.
The bile acid or bile acid salt content of the emulsion of t
Fukui Hiroshi
Seki Junzo
Kishore Gollamudi S.
Nippon Shinyaku Co. Ltd.
Rzucidlo Eugene C.
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