Fat emulsions for inhalational administration

Details Fat emulsions for inhalational administration Fat emulsions for inhalational administration

2000-08-30

2003-04-08

Dees, Jose G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S450000, C424S400000, C424S489000, C424S046000

Reexamination Certificate

active

06544542

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a medical o/w fat emulsion containing a drug for inhalational administration.
BACKGROUND ART
As a technique for administering a drug to a human body, the method is known which comprises generating a finely divided mist of aerosol particles from a solution containing a drug by means of an inhaler such as a nebulizer and causing the mist to be inhaled from the nasal or oral cavity.
To carry out this method, the drug must be dissolved in water in advance but in the case of a drug which is hardly soluble in water, the drug must be solubilized with a surfactant or the like. However, even if an attempt is made to administer a medical solution prepared by such solubilization with a surfactant as an inhalant using an inhaler such as a nebulizer, it may not be easily administered by this route because such a solution may be irritating or produce a foam.
Another method known for inhalation therapy comprises dissolving a drug in a fat emulsion having a comparatively large vesicle size known as the lipid microsphere and causing it to be inhaled by means of an inhaler such as a nebulizer [e.g. JP Kokai H5-70346, JP Kokai H5-124965, JP Kokai H8-301762]. However, because such fat emulsions have a comparatively high viscosity and the diameter of emulsion vesicles is as large as 0.2~0.4 &mgr;m on the average, a finely divided aerosol mist such as one having a mass median aerodynamic diameter (MMAD) of 0.5~5 &mgr;m and as such capable of reaching the pulmonary alveolus can hardly be produced even if an inhaler such as a nebulizer is employed. An additional disadvantage of these emulsions is that because of the large emulsion vesicle size, those emulsions cannot be sterilized by filtration using a 0.22 &mgr;m membrane filter.
DISCLOSURE OF INVENTION
The object of the present invention is to provide a pharmaceutical composition optimized for the administration of a drug, particularly a drug which is only sparingly soluble in water, by way of inhalation.
The inventors of the present invention found after much research that an ultrafine o/w fat emulsion comprising a dispersion of fat emulsion particles as fine as the order of tens of nanometers is extremely suited for the inhalation of drugs and have developed the present invention.
The present invention, therefore, is directed to a fat emulsion for inhalant use in the form of an o/w fat emulsion comprising fat emulsion particles essentially composed of an oil component, an emulsifying agent and a drug as dispersed in water, the average particle diameter of said fat emulsion particles being within the range of 5~100 nm (hereinafter referred to as the inhalant of the invention), or a lyophilized composition thereof for inhalant use. The present invention further encompasses a method for administering a fat emulsion by way of inhalation, said fat emulsion being an o/w fat emulsion comprising fat emulsion particles essentially composed of an oil component, an emulsifying agent and a drug as dispersed in water and the average particle diameter of said fat emulsion particles being within the range of 5~100 nm, or a method for administering a lyophilized composition thereof by way of inhalation.
The present invention is now described in detail.
The oil component which can be used in the present invention is not particularly restricted inasmuch as it is an oil component which can be used in pharmaceutical preparations and includes but is not limited to vegetable oil, animal oil, neutral lipid (mono-, di- or tri-substituted glyceride), synthetic lipid, and sterol derivatives. To be specific, the vegetable oil includes soybean oil, cottonseed oil, rapeseedoil, sesame oil, corn oil, peanut oil, safflower oil, etc.; the animal oil includes fish oil, among others; the neutral lipid includes triolein, trilinolein, tripalmitin, tristearin, trimyristin, triarachidonin, etc.; the synthetic lipid includes azone, among others; the sterol derivative includes cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palpitate, cholesteryl arachidate, and so on. These may be used each alone or in a combination of two or more species. The preferred oil component includes triglycerides and vegetable oils composed predominantly thereof. For all practical purposes, soybean oil is preferred and highly purified soybean oil (preferably with a glyceride content of 99 weight % or more) is particularly useful.
The level of said oil component in the inhalant of the invention should vary with the species of oil and other components and may typically be 0.1~30 w/v %, preferably 1~20 w/v %.
The emulsifier which can be used in the present invention is not particularly restricted inasmuch as it is pharmaceutically acceptable and may for example be a phospholipid or a nonionic surfactant. The phospholipid includes but is not limited to phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, sphingomyelin and lecithin. Hydrogenated phospholipids may also be employed. The nonionic surfactant includes 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, do(40) ether, do(100) ether, etc.), and castor oil polyoxyalkylene derivatives (e.g. castor oil polyoxyethylene(20) ether, do(40) ether, do(100) ether, etc). These can be used each alone or in a combination of two or more species. The preferred emulsifying agent includes egg yolk phosphatidylcholine, egg yolk lecithin and soybean lecithin, among others. For practical purposes, egg yolk lecithin and soybean lecithin are preferred.
The level of said emulsifier in the inhalant of the invention should vary with the species of emulsifier and other components but may appropriately be 0.05~40 w/v %, preferably 0.1~20 w/v %.
The oil component-to-emulsifying agent (oil/emulsifier) ratio by weight may be 0.1~20, preferably 0.4~6.0, more preferably 0.8~1.2 (particularly 1).
The drug which can be used in the present invention is not particularly restricted but is preferably a drug which is more readily lipid-soluble than water-soluble. As such drugs, the so-called lipid-soluble drugs and water-insoluble drugs can be mentioned. Included among them are central nervous system drugs, peripheral nervous system drugs, sensory organ drugs, cardiovascular system drugs, respiratory system drugs, hormones, urogenital system drugs, drugs for anal diseases, vitamins, drugs for liver diseases, antigout drugs, enzymes, antidiabetics, immunosuppressants, cytoactivators, antitumoral drugs, radioactive drugs, antiallergic drugs, antibiotics, chemotherapeutic agents, biological drugs, and extracorporeal diagnostic agents.
More particularly, the following drugs can be mentioned by way of example.
1. Steroidal Drugs
Dexamethasone, prednisolone, betamethasone, beclomethasone propionate, triamcinolone, hydrocortisone, fludrocortisone and prasterone, salts thereof, and their lipid-soluble derivatives.
2. &bgr;-Adrenergic Agonists
Procaterol, orciprenaline, isoproterenol hydrochloride, pirbuterol, terbutaline, hexoprenaline, fenoterol hydrobromide, hexoprenaline sulfate, terbutaline sulfate, salbutamol sulfate, oxyprenaline sulfate, formoterol fumarate, isoprenaline hydrochloride, pirbuterol hydrochloride, procaterol hydrochloride, mabuterol hydrochloride, and tulobuterol, salts thereof, and their lipid-soluble derivatives.
3. Xanthine Derivatives
Diprophylline, proxyphylline, aminophylline and theophylline, salts thereof, and their lipid-soluble derivatives.
4. Antibiotics
Pentamidine isethionate, cefmenoxime, kanamycin, fradiomycin, erythromycin, josamycin, tetracycline, minocycline, chloramphenicol, streptomycin, midecamycin, amphotericin B, itraconazole and nystatin, salts thereof, and their lipid-soluble derivatives.

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