Title:  Fat emulsions for inhalational administration

United States Patent:  6,544,542

Issued:  April 8, 2003

Inventors:  Sonoke; Satoru (Kameoka, JP); Seki; Junzo (Ibaraki, JP)

Assignee:  Nippon Shinyaku Co., Ltd. (Kyoto, JP)

Appl. No.:  623331

Filed:  August 30, 2000

PCT Filed:  March 3, 1999

PCT NO:  PCT/JP99/01004

PCT PUB.NO.:  WO99/44594

PCT PUB. Date: September 10, 1999

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 present invention is a fat emulsion for inhalational administration, or a lyophilized composition thereof, which is 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, characterized in that the average particle diameter of said fat emulsion particles lies within the range of 5.about.100 nm. With the aid of a suitable inhaler, the inhalant of the invention readily yields a mist of aerosol particles fine enough to reach the alveolus; the inhalant is well amenable to size control of the aerosol particles.

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.about.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.about.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.about.30 w/v %, preferably 1.about.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.about.10000, preferably 4000.about.6000) , polyoxyalkylene copolymers (e.g. a polyoxyethylene-polyoxypropylene copolymer with an average molecular weight of 1000.about.20000, preferably 6000.about.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.about.40 w/v %, preferably 0.1.about.20 w/v %.

The oil component-to-emulsifying agent (oil/emulsifier) ratio by weight may be 0.1.about.20, preferably 0.4.about.6.0, more preferably 0.8.about.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. .beta.-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.

5. Others

Ipratropium bromide, methylephedrine hydrochloride, trimethoquinol hydrochloride, clenbuterol hydrochloride, oxitropium bromide, fultropium bromide, methoxyphenamine hydrochloride, chlorprenaline hydrochloride sodium cromoglycate.

The formulating level of the drug in the inhalant of the invention varies with the species of drug and other components but may suitably be 0.05.about.20 w/v %.

Furthermore, in the present invention, a co-emulsifier and/or an emulsion stabilizer can be formulated. The co-emulsifier and/or emulsion stabilizer includes straight-chain or branched-chain saturated or unsaturated fatty acids containing 6.about.22 carbon atoms, such as stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, etc. and salts thereof [e.g. alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts etc.)]; primary or secondary aliphatic amines containing 2.about.22 carbon atoms, such as ethanolamine, propylamine, octylamine, stearylamine, oleylamine, etc.; basic amino acids such as lysine, histidine, ornithine, arginine, etc.; sterols such as cholesterol, cholestanol, etc.; and charged substances such as phosphatidic acid, ganglioside, stearylamine, etc. These may be used each alone or in a suitable combination of two or more species.

The formulating level of these substances depends on the objective to be achieved but may generally be not more than 2 w/v %, preferably not more than 1 w/v %.

In addition, pharmaceutically acceptable additives such as the antioxidant, preservative, isotonizing agent, buffer, stabilizer, etc. as well as adjuvants and nutrients may also be formulated. Specifically, benzoic acid, ascorbic acid, and tocopherol can be mentioned. These can be added generally in a suitable amount and need not be more than 10 w/v %.

The average particle diameter of the fat emulsion according to the present invention is 5.about.100 nm, preferably 5.about.70 nm, more preferably 10.about.50 nm. Also preferred is a fat emulsion with not less than 90% of fat emulsion particles falling within the particle size range of 5.about.100 nm.

While the fat emulsion particles of the inhalant of the present invention disperse in water, the water may for example be tap water, purified water, distilled water, water for injection, an electrolyte solution such as saline or a glucose solution.

The inhalant of the present invention can be freeze-dried to give a lyophilized composition. When it is to be provided in the form of such a lyophilizate, a suitable excipient is preferably formulated for the purpose of protecting freeze-dried fat emulsion particles, and/or the so-called freeze-dried cake. Such excipient includes saccharides, preferably disaccharides, specifically maltose, trehalose and sucrose. Particularly preferred is maltose.

The formulating level of said excipient in the inhalant of the invention varies with the species of excipient and other components but may suitably be 1.about.30 w/v %, preferably 3.about.20 w/v %.

The inhalant of the present invention can be manufactured by the known technology for the production of an ultrafine fat emulsion, i.e., Lipid Nanosphere [e.g. JP Kokai H2-203, JP Kokai H1-143826, JP Kokai H1-249716]. A typical process may comprise adding a drug, an emulsifier and other additive components in suitable amounts to a given quantity of an oil component, optionally heating the mixture for homogenization, adding a suitable amount of water and emulsifying the whole mixture with a conventional emulsifying machine such as the homomixer, homogenizer, ultrasonic homogenizer, Microfluidizer (tradename), Nanomizer (tradename), Ultimizer (tradename), or Manton-Gaulin high-pressure homogenizer until a predetermined particle size is attained. The emulsification can be carried out in two divided stages, namely preliminary emulsification and final emulsification.

The inhalant of the present invention can be filtration-sterilized by means of a 0.22 .mu.m membrane filter.

The lyophilized inhalant of the present invention can be manufactured by freeze-drying said inhalant of the invention by the conventional procedure (e.g. PCT WO92/07552, JP Kokai H5-43450, JP Kokai H6-157294). For example, the inhalant of the invention is sterilized and distributed into vials. The vials are then subjected to preliminary freezing at about -40.about.-20^oC. for about 2 hours, primary drying under reduced pressure at 0.about.10^oC., and secondary freeze-drying under reduced pressure at about 15.about.25^oC. The subsequent procedure generally comprises nitrogen gas purging and closing the vials to provide the lyophilized inhalant of the invention.

The inhalant of the invention can be administered to the human body through the nasal or oral cavity by generating aerosol particles of the inhalant with the aid of a device capable of generating an aerosol of an appropriate mist size according to the administration site (the upper respiratory tract, bronchioles, peripheral airways or alveolus) or the therapeutic objective (for the therapy of inflammation or for bronchodilation). The device for generating aerosol particles of the inhalant of the invention is not particularly restricted inasmuch as it is capable of producing aerosol particles 0.5.about.50 .mu.m in diameter but is preferably a device adapted to generate an aerosol mist having a mass median aerodynamic diameter of 0.5.about.5 .mu.m, particularly 1.about.2 .mu.m. As specific examples of such device, there can be mentioned pressure nebulizers and ultrasonic nebulizers. Therefore, the present invention encompasses a nebulizer preparation comprising the inhalant of the invention. The inhalant of the invention may also be provided in the form of an inhalation aerosol preparation comprising the inhalant of the invention.

The lyophilized composition of the present invention can be applied to the human body by the airway route using an inhaler such as a nebulizer after it is reconstituted with an arbitrary suitable solution (a reconstitution medium) with or without agitation. The reconstitution medium which can be used in this manner includes tap water, purified water, distilled water, water for injection, an electrolyte solution inclusive of saline, a glucose solution, a standard infusion and drinking water, among others. The volume of the reconstitution medium is not particularly restricted but may suitably be 0.5.about.2 times as much as the volume of the pre-lyophilization solution or not more than 500 ml. Thus, the nebulizer preparation comprising a lyophilized form of the inhalant of the invention also falls within the scope of the present invention.

Furthermore, the lyophilized composition of the present invention can be micronized and directly inhaled in a finely divided form with the aid of a suitable inhaler such as a spinhaler or a diskhaler. Therefore, the present invention encompasses a powdery inhalant comprising the lyophilized composition of the invention.

With the aid of a suitable inhaler, the inhalant of the invention is capable of delivering the drug entrapped in its fat emulsion vesicles far enough to the pulmonary alveolus so that, depending on the intravascular migration efficiency of the fat emulsion particles, for instance, it can be indicated even when a systemic effect is desired.

Claim 1 of 12 Claims

What is claimed is:

1. A medical fat emulsion for inhalational administration to an individual, or a lyophilized composition thereof, wherein said emulsion is an o/w fat emulsion comprising an aqueous dispersion of uniform and spherical ultrafine fat emulsion particles essentially composed of an oil component, a phospholipid and a sparingly water-soluble medical drug, wherein the average particle diameter of said fat emulsion particles is within a range of 5-100 nm.
 

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