KR20010033040A - Pharmaceutical Compositions for Mucolysis and Treatment of Inflammation - Google Patents

Abstract

The present invention relates to the use of formula (I) to reduce inflammation in mammals and to reduce the viscosity of mucus.

<Formula I>

In the formula,

One of X, Y, or Z Indicates

Each R represents hydrogen or methyl and the other two of X, Y or Z each represents -CO-R ¹ , wherein R ¹ is unsubstituted or halo, C _1-6 straight or branched alkoxy, or cyano A straight or branched C _11-21 alkyl or C _11-21 alkenyl substituted with one or more substituents selected from the group consisting of:

Description

Pharmaceutical Compositions for Mucolysis and Treatment of Inflammation

For example, some drugs have been reported that appear to have a beneficial effect on airway cleansing of mucous membranes through their effect on cilia or by changing the physical properties of mucus secretions. One class, represented by a saturated solution of iodide, for example potassium iodide or glycerol iodide, is believed to stimulate the secretion of "diluent" secretions that are easier to clean. Another class is represented by N-acetyl cysteine. The viscosity of the pulmonary mucus secretion mainly depends on the concentration of the mucus protein, and the free sulfhydryl group of N-acetyl cysteine was believed to open the mucus protein disulfide bonds and reduce the viscosity of the mucus. For a review of mucolytic drugs, see P.C. Braga: Drugs in Bronchial Mucology, Raven Press, New York, 1898.

Inflammation accompanying diseases, including increased mucous secretions, is a syndrome that also spreads over a wide range of events, including trauma, many bacterial and viral infections, allergic and immunogenic reactions, and autoimmune diseases as well. . Rapid and effective treatment of inflammation is required to minimize the possibility of secondary injury in the patient due to the patient's anxiety and the inflammation itself.

Inflammation in the lungs, as well as in the skin, eyes, mucous membranes (oral and nose) and other aspects of the body, including the anal / rectal / perineal region, can be treated locally by administering suitable anti-inflammatory agents. The present invention relates to the use of a medicament which is a phospholipid compound and a topically administered compound, which is a mucolytic and anti-inflammatory agent.

U.S. Pat.No. 4,421,748 (patented December 20, 1983) to Trager and Kylinsky describes the use of artificial oils containing a sterile aqueous reservoirable solution of lecithin and a viscosity modifier. Topical administration is described. Lecithin is phosphatidylcholine, which is a mixture of diglycerides of stearic acid, palmitic acid and oleic acid bound to choline ester residues. It is found in all organic organisms and is an important component of nervous tissue.

US Pat. No. 4,914,088 to Glonk et al describes a method of treatment of dry eye in which the charged phospholipids are administered to the eye.

A 1994 research report by Thomassen et al. [Am. Respir. Cell Mol. Biol. 10: 399-404, data showing that dipalmitoyl-phosphatidylcholine (DPPC) does not affect alveolar macrophage secretion.

<Summary of invention>

It is an object of the present invention to provide a method for reducing the viscosity of pulmonary mucus and inflammation in the lung airways.

Another object of the present invention is to improve the removal of accumulated mucus in patients with excessive secretion of mucus.

It is a further object of the present invention to provide a method for ameliorating various lung diseases including airway obstruction due to accumulated mucus secretions associated with inflammation.

Another object of the present invention is to provide a composition for topical treatment of a mammal, including topical treatment of skin, eye, nose and lung passages, anus and rectum.

The present inventors have now found that the phospholipids of formula (I) exhibit significant local anti-inflammatory and mucolytic activities without being bound to any particular model of action.

In the formula,

One of X, Y, or Z Indicates

Each R group independently represents hydrogen or methyl (preferably a compound in which all three R groups are methyl),

The other two of X, Y or Z are each independently —CO—R ¹ wherein R ¹ is unsubstituted or halo (ie, fluoro, bromo, chloro or iodo), C _1-6 straight or branched Linear or branched C _11-21 alkyl or C _11-21 alkenyl substituted with one or more (preferred) substituents selected from the group consisting of chain alkoxy, or cyano). It dog -CO-R ¹ group 2 the same is preferred.

Phospholipids of formula I of the present invention contain optically active carbon at the 2-position of the glycerol backbone. All optical isomers in which an optical center is present in the side chain R ¹ are considered to belong to the present invention. The geometric isomers formed when R ¹ is alkenyl also belong to the invention.

Preferred phospholipids of formula (I) and all isomeric forms thereof are represented by formula (II).

Wherein R and R ¹ are as defined above.

Most preferred phospholipids of Formula I are dipalmitoyl phosphatidylcholine (DPPC) (also known as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and distearoyl phosphatidylcholine (DSPC) (1, 2-dstearoyl-sn-glycero-3-phosphocholine). The natural isomer of DPPC is dipalmitoyl-L-alpha-phosphatidylcholine.

As another representative phospholipid of formula (I),

1,2-palmitoyl-sn-glycero-3-phosphoethanolamine

1,3-palmitoyl-sn-glycero-2-phosphocholine,

1,2-dstearoyl-sn-glycero-3-phospho- (N-methyl) ethanolamine,

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine,

1,3-stearoyl-sn-glycero-2-phospho- (N, N-dimethyl) ethanolamine,

1,2-dilauroyl-sn-glycero-3-phosphocholine,

1,2-diecosanoyl-sn-glycero-3-phosphocholine,

1-oleyl-3-myristoyl-sn-glycero-3-phospho- (N-methyl) ethanolamine,

1,2-di- (9-chloro-octadecanoyl) -sn-glycero-3-phosphocholine,

1,2-di- (9-octadekenoyl) -sn-glycero-3-phosphocholine,

1,2-di- (8-cyano-hexadecanoyl) -sn-glycero-3-phosphocholine,

1,3-di (9-hexadekenoyl) -sn-glycero-2-phosphocholine, and

1,2-di- (8-methoxy-hexadecanoyl) -sn-glycero-2-phosphocholine.

<Detailed Description of Drawings>

1 is a graph showing respiratory explosion in Raw 264.7 cells induced with PMA in the presence of DPPC.

2 is a graph showing the effect of various concentrations of DPPC on inflammation on PMA induced ear edema in mice.

3 is a graph showing the results of study over time for the inhibition of PMA induced ear edema in mice treated with DPPC.

The present invention relates to the field of topical treatment of mucus dissolution and inflammation, and in particular to the use of certain mucolytic agents in diluting or lowering the viscosity of tacky mucus, which is a tacky secretion of the mucosa. Such agents reduce the viscosity and inflammation of mucous secretions, thereby increasing the efficiency of reflex coughing and ciliary action upon removal of accumulated mucosal secretions from the lung airways.

Phospholipids of formula (I) and methods for their preparation are known in the literature, some of which are commercially available, including the most preferred DPPCs and DSPCs. See, for example, US Pat. Nos. 4,814,112 and 4,622,180 (Hansen et al., Lipid (1982), 17, 453-459; Murari et al., J. Org. Chem., (1982), 47, 2158-2163; Lammers et al., Chem. Phys. Lipids (1978), 22, 293-305; Eibl et al., Liebigs Ann. Chem. (1967), 709, 226-230; and Okazaki ( Okazaki et al., Bull. Chem. Soc. Jpn. (1981), 54, 2399-2407).

Dipalmitoyl phosphatidylcholine (DPPC) is the main component (about 80%) of the body's natural lung surfactant. Lung surfactants are substances that are routinely secreted from the surface of alveoli. Lack of pulmonary surfactants is known to cause respiratory distress syndrome (RDS) in premature infants and infants. This deficiency is not a major factor in adult respiratory distress syndrome (ARDS) but may be a major cause of the pathophysiology of the disease.

RDS is the leading cause of death and disability in premature infants. In addition, 150,000 cases of ARDS have been reported to produce 60-80% mortality annually. Numerous natural surfactants (human and bovine) and fully synthetic surfactants are administered to the lungs of human patients, for example, by inhalation of the spray composition to treat RDS and ARDS.

Generally, most synthetic inhalation surfactant compositions include DPPC because it is known that DPPC can improve respiratory function in RDS and ARDS patients. This is because lowering the surface tension of the alveoli makes the exchange of oxygen and carbon dioxide easier. In general, for example, US Pat. No. 5,299,566, which is incorporated herein by reference, discloses a process for preparing a surfactant dispersant containing DPPC; US Pat. No. 5,110,806, which discloses synthetic surfactants containing DPPC, higher alcohols and nonionic surfactants; US Pat. No. 4,765,987, which discloses synthetic surfactants containing DPPC, DSPC and soy lecithin; United States Patent Nos. 4,571,334 disclose combinations of various drugs of pulmonary surfactants; See US Pat. No. 4,312,860, which discloses synthetic surfactants containing DPPC and fatty alcohols.

However, Applicants do not know that DPPC or any other embodiment of Formula I phospholipids underlying the present invention has been reported to have mucolytic or anti-inflammatory activity. We have found that the phospholipid I of the present invention reduces the viscosity of the sticky mucus to promote removal of viscous concentrated mucus from the lung airways and also reduces inflammation. The result is improved mucus discharge in the bronchus and trachea, and also relieves congestion in acute or chronic lung disease due to excessive mucus accumulation in the lungs and upper respiratory tract.

Accordingly, the present invention provides a method for alleviating breathing difficulties due to these causes in patients suffering from sticky lung mucus secretion and inflammation, especially breathing difficulties due to non-alveolar type (ie, in the airways, bronchial tubes and bronchioles). The method can be readily performed using intermittent inhalation of an aerosol that delivers an effective mucolytic amount of Formula I phospholipid to the lung airways.

The compounds of formula (I) may also be used in any disease state that is caused by or is a major factor in inflammation including bronchial asthma, bronchitis, cystic fibrosis, rheumatoid arthritis, psoriasis, immediate and delayed hypersensitivity, conjunctivitis, rhinitis, hemorrhoids It is useful for topical treatment.

"Topical application" can be applied topically on the skin, conjunctiva, mucous membranes, oral mucosa or by contact with the pulmonary through inhalation or contact with the rectal membrane as an enema or suppository.

Dosing and Pharmaceutical Compositions

Effective amounts of the compounds of formula (I), of course, vary with the mammal being treated and with the condition causing the inflammation, and ultimately at the discretion of the physician or veterinarian. The factors to be treated include the condition to be treated, the route of administration, the nature of the composition, the weight, age and general conditions of the mammal, and the particular compound to be administered.

Generally, the compound is applied by adding lithium to the lesion. Individual metered doses, however, should be within the scope of the present invention and, if desired, can be administered to individual patients by monitoring reduction in inflammation corresponding to known doses of the drug.

Generally, pharmaceutical compositions comprising a compound of formula (I) contain from about 1.0% to 100% of one or more compounds of formula (I) as active ingredients. Where the active ingredient is less than the total composition, the remainder comprises carriers pharmaceutically suitable for topical administration and other auxiliary ingredients such as emulsifiers, desiccants, colorants, fragrances, stabilizers, flow promoters, etc., well known in the topical pharmaceutical industry. It is done.

Preferred pharmaceutical compositions containing a compound of formula (I) are in liquid or semi-liquid form, such as solutions, suspensions, emulsions, gels, lotions, creams, ointments, suppositories, and the like, using conventional topical carriers. Conventional aerosol compositions and methodologies are used for inhalation therapy.

Mucolytic Activity:

Mucolytic activity of the phospholipids of the present invention is shown by standard ex vivo and in vivo assays using bovine airway mucosa and animal models, respectively. In vitro analysis, bovine airway mucus was mixed with DPPC, DSPC or other phospholipids of Formula I and dissolved to allow the mucosa to flow in greater volume than when only vehicle (saline) was used. In vivo mucolytic assays were similar to those described in Chand et al. (1993), Agents and Actions, 38: 165-170, incorporated herein by reference (in particular, the evaluation of mucous activity in mice is 166). See after page). More detailed descriptions of the in vitro and in vivo assays are provided in the Examples below. The results exemplified by the test compound, DPPC, show mucolytic activity equivalent to N-acetylcysteine, a known mucolytic substance.

Aerosolic delivery of the drug to the lung airways has been used in clinical trials for many years. Various agents, including, for example, synthetic surfactant compositions containing N-acetylcysteine and DPPC and DSPC, have been used in aerosol therapy for the treatment of RDS and ARDS patients. The advantage of an aerosol delivery system is that the drug spreads widely throughout all parts of the lungs over time.

Phospholipids of formula (I) tend to be used as dispersants in usable nebulized liquid compositions such as, for example, administration with simple nebulizers or metered dose inhalers. Phospholipids of the present invention may also be prepared as dispersants in sterile lyophilized powders of suitable average diameter for direct inhalation or as powders that are reconstituted with an aqueous carrier such as saline of water or preferably about 0.4 to about 0.9% sodium chloride. Which is delivered via a suitable simple nebulizer or inhalation system. The preferred average diameter of the particle dispersion powder is about 1 to 10 micrometers (microns) on any axis, preferably about 5 to 10 micrometers. Phospholipids are generally included in general or weakly storage saline at about 0.1 to 10 w / v% with propellants known in the art such as, for example, dichlorodifluoromethane and present in metered dose spray units. In each spray, 0.1 to 100 mg of phospholipid I is ejected.

Techniques for making spray drug delivery systems are well documented. Phospholipids of formula (I) are included in such systems according to methodologies recognized in the art that need not be repeated in detail herein. In fact, as previously described, the spray surfactant composition contains DPPC and DSPC, the formulations of which have previously been described as RDS and ARDS therapeutics and similar aerosol methods are used in the present invention.

According to the invention the phospholipid I of the invention is used as an inhalant for the treatment of respiratory diseases in which inflammation and mucus viscosity or accumulated mucus are the main problem. Such diseases may include chronic bronchitis, cystic fibrosis, and asthma (see American Thoracic Society, Symposium Excerpts, 1994 International Assembly). Chronic impaired pulmonary disease is also associated with increased mucus secretion (see Ferguson and Chermiak (1993) COPD Management, New. Eng. J. Med., Pp. 1017-1021). The present invention does not apply to the treatment of RDS or ARDS as these respiratory hard diseases are characteristically alveolar and not characterized by thickened or accumulated mucus secretion.

Phospholipids I of the present invention may be used alone or in combination with other mucolytic agents suitable for aerosolic delivery to the alveoli of the airways, lungs and / or other active ingredients such as, for example, antibiotics, bronchodilators.

Anti-inflammatory activity:

Inflammation is a complex process involving various cell types, including macrophages. See, for example, S. L. Kunkel et al. (“Inflammatory Cytokines”, pp. 1-15, in the Handbook of Vascular Mediators), P. A. Ward (editor, published by Hospital Practice Press). References to macrophages are described by Ralph and Nakoinz (J. Immunology (1977) 119: 950-954) and Raschke et al. (Cell (1978) 15: 261-267. There are so many, including).

Macrophages are activated by infection and a wide variety of non-infectious stimuli and inflammation inducers. When activated, macrophages participate in various reactions. They surround bacteria and kill them with oxygen-dependent or oxygen-independent pathways. Oxygen-dependent pathways in which activation of macrophages leads to increased oxygen consumption and produces reactive oxygen species (eg radicals such as superoxides). The production of reactive oxygen species by activated macrophages is associated with the inflammatory response. Macrophages are also activated to secrete various inflammatory cytokines, including several interleukins and tumor necrosis factor α (TNF-α). Inhibiting any of these activity-related processes reduces the inflammatory response.

For this reason, the activation of macrophages is very important for the study of inflammatory processes, and substances that reduce macrophage activation are used as anti-inflammatory agents.

The anti-inflammatory activity of the compounds of formula (I) can be analyzed using many methods conventional in the art. Two inflammatory models of macrophage activation and mouse ear edema were used in the examples below to demonstrate the anti-inflammatory effect of the compounds of the invention.

The following examples use DPPC to illustrate their purpose and illustrate the invention but do not limit its scope.

<Example 1>

Mucolytic activity in organ tracheal mucus

The tracheal mucus was scraped slightly from freshly slaughtered cows from a local slaughterhouse. Under fixed isothermal conditions, the mucus was mixed with physiological saline at a ratio of 1: 5 (mL) and sonicated for 1 minute. 1 mL of this mixture was added to 1 mL of test compound or control saline and sonicated again for 1 minute. Five minutes after sonication, 1 mL of the sample solution was pipetted into a 3 mL syringe with a 18 g × 4.04 cm (1.5 inch) needle and attached vertically to the ring stand. At time zero the syringe cap was removed and the time of passage of the mucus flowing along the syringe / needle combination was recorded. The results are shown below:

compound Final concentration Transit time Saline Control Control 3 minutes 32 seconds DPPC 5mg / mL 2 minutes 20 seconds

The results show that DPPC has a direct mucolytic effect on bovine airway mucus. Similar results were obtained from DSPC.

<Example 2>

Mucolytic Activity in the Mouse Organ Mucosa

The method of delivering test compounds to mice in nebulized form is a modified assay for evaluating mucolytic activity in mice as described by Chand et al.

1. The test animals are Hsd: 1CR (CD-1) mice, each weighing approximately 25 g.

2. Dilute the test compound to normal saline at a concentration of 25 mg / ml, and approximately 100 mg / kg of human de Vilbiss atomizer Model No. 15 was administered. Saline was given to the control. The nozzle was installed in the mouth of the mouse and sprayed twice.

3. After 30 minutes, phenol red dissolved in a 5% solution in saline was administered intraperitoneally at a dose of 0.1 ml per 10 g of body weight.

4. 30 minutes after phenol red administration, animals were sacrificed by exposure to 100% CO ₂ .

5. The entire organ was removed, the outside was blotted dry, and the organ was washed with 1.0 ml saline. After 30 minutes, 0.1 ml of 1 M NaOH was added to the tracheal wash to stabilize the pH of the wash.

6. The amount of phenol red secreted into the organ was quantified by photometry at 546 nm.

7. The delivered dose was measured as five sprayed volumes per tube in five individual tubes. The average dose was 60.4 μl per spray, ranging from 58 to 63 μl.

As a result of the test, the rate of change of the mucolytic activity was determined to be about 58% for DPPC, compared to about 62% for N-acetylcysteine and 0% for control saline.

<Example 3: Respiration Cartridge>

ingredient Usage Per Cartridge DPPC 5.0 mg Lactose, moderate amount 25.0 mg

The active ingredient, DPPC, was pre-micronized to a particle size of 10 to 50 microns in average diameter and blended with normal tablet grade lactose with a high energy mixer. The powder blend was granulated to a particle size of 1 to 10 microns and filled into hard gelatin capsules or cartridges of suitable size with a suitable encapsulation machine. A powder inhaler was used to administer the respirable content of the capsule or cartridge.

Example 4 Measurement of Liquid Dose

ingredient Usage Per Cartridge DPPC 5.0 wt% Isotonic saline A reasonable amount

The active ingredient, DPPC, was dissolved in a sufficient amount of isotonic sterile saline to give a 5% by weight DPPC solution. The solution was administered at a nebulized metered dose using a suitable nebulizer.

Example 5 In Vitro Assay for Anti-inflammatory Activity Through Inhibition of Macrophage Activity

The activity of alveolar macrophages is a critical factor in lung inflammation. When they are active, alveolar macrophages secrete a variety of inflammatory mediators and reactive oxygen compounds. In this in vitro model for inflammation, mouse macrophages are activated by Phobol-12-myristate-13-acetate (PMA). The intensity of macrophage activity in the presence or absence of DPPC is determined by measuring the respiratory explosion (for reactive oxygen compounds) of macrophages.

The RAW 264.7 cell line (Accession No. TIB 71 of the American Type Culture Collection, Rockville, MD) is a mononuclear / macrophage system in rats, which is characterized by a variety of macrophages. It is a cell that exhibits function. Like macrophages, these cells are capable of phagocytosis and perform oxidative explosion (increased oxygen consumption) and production of oxygen radicals (eg, peroxides) in response to appropriate signals. Agents that inhibit the activity of these cells in vitro in order to inhibit the respiratory explosion associated with activity and the production of corresponding oxygen radicals interfere with an important step in the inflammatory process.

Respiratory explosions that activate macrophages and the production of corresponding oxygen radicals have been described in Chemiluminescence by Phagocytic Cells, based on the reaction of oxygen radicals with luminol added to the medium (MA Trush et al. , Methods in Enzymology 57: 462-494, 1997). Chemiluminescence generated from luminol in the media of macrophages is recognized by those skilled in the art as an indicator of macrophage activity.

material:

Cell line: Raw 264.7 (ATCC TIB-71, dependently attached);

Medium: Dulbecco's Modified Eagle's Medium (DMEM, Sigma Chemical Co. Cat. No. D-7777) containing 10% fetal bovine serum;

Standard protocols for cultured cell lines: T-75 or T-150 flasks; 95% air, 5% CO ₂ ; 100% relative humidity.

When joining trypsin (1 mg / ml) and ethylenediamine tetraacetic acid (EDTA) (1 μM in Ca-Mg glass Hank balance salt solution) split 1: 4 to 1: 5 at approximately 80%, Passed through the cell line.

All procedures were performed aseptically in a Class II biological safety cabinet using standard biosafety level 2 (BL-2) inhibition procedures. To prevent genetic variation in colony cell lines, fresh medium was prepared from activated liquid cells from stored liquid nitrogen at approximately one month intervals.

Way:

After passing through the cells, count the cells with a hemocytometer,

Adjust the cell concentration to approximately 1,000,000 cells per ml,

Cells are suspended in DMEM lacking phenol red and FBS,

1 ml of cell suspension is pipetted into a standard luminescent cuvette (12 × 75 mm, purchased from Analytical Luminescence Laboratory, San Diego, CA),

Add luminol to a final concentration of 0.2 μM,

Test compound is dissolved in phosphate buffered saline (PBS) or dimethyl sulfoxide (DMSO) to a final concentration in the range of 0-30 μM,

Add 100 nanograms of four-ball myristate acetate (PMA),

After waiting for 1 minute, the number of lights (ie luminescence values) on the Monolight 2010 luminometer purchased from a luminescence analysis laboratory in San Diego was read.

Data analysis:

Background conditions-no test compound, no PMA,

Control-no test compound,

Calculation:

% Inhibition =

1-L (Test Compound)-L (Base Condition) / L (Control) -L (Base Condition) x 100

Where L is the light emission value (breathing explosion).

result:

As shown in FIG. 1, the dose-response curve for DPPC in the presence of 1 nM PMA, DPPC utilizes PMA and the resulting respiratory blast to effectively inhibit macrophage activity. Similar results were obtained by DSPC. These results indicate that compounds of formula I act as anti-inflammatory agents in the airways.

Example 6 In Vitro Assay for Anti-inflammatory Activity by Mouse Ear Edema

A typical in vitro model for evaluating anti-inflammatory agents is pobol myristate acetate (PMA) induced inflammation in mouse ears. This method is described in "Pharmacological Method in the Control of Inflammation", Joseph Y. Chang and Alan J. Lewis (Editor), Alan R., New York. Inc. (Alan R. Inc.), pp. 221-223 (1989). This analysis quantified the edema characterized by inflammation by measuring ear thickness or ear weight approximately 6 hours after PMA was applied to the ear.

material:

Mice: 21-24 g (production number 3002) male CD-1, obtained from Harlan Sprague Dawley, Indianapolis, Indiana, USA

Way:

0.01% (w / v) of PMA in an equal volume of acetone and ethanol mixture containing 0 (excipient), 1%, 2.5% or 5% of the test compound,

Prepare an excipient solution of the same volume of acetone and ethanol,

To prepare a control solution of 0.01% (w / v) of PMA in the same volume of acetone and ethanol mixture containing 1% dexamethasone,

Divide the mice into 3 groups,

One of the solutions was treated in the right ear of each group of mice using a micropipette,

After waiting 6 hours, the mice are euthanized in a CO ₂ chamber,

Cut the ears and drill them into a 6-mm diameter circle,

Weigh three appropriate pieces of ear per same group,

Measure the average weight of all untreated ear samples (average weight of control ear),

The average weight of the test ear samples of each group (mean weight of the test group ears) was measured.

The average weight increase rate of the ears was calculated as follows.

% Weight increase of ears =

Average weight of test group ears—average weight of control ear / average weight of control ear × 100.

result:

2 and 3 show the results of a series of studies on the anti-inflammatory properties of DPPC. As shown in FIG. 2, a single dose of 5% of this compound is not effective for ear edema. At 10%, single doses of DPPC inhibited ear edema at 34%. When 5% DPPC was administered once with PMA and once after 20 minutes, ear edema was reduced to 54%. However, there was no substantial effect on ear edema if PMA was treated once 20 minutes before and PMA was treated again.

3 demonstrates that ear edema is inhibited by 72% when DPPC is repeatedly treated during the first 2 hours of inflammatory response to PMA. Since DPPC is a naturally occurring molecule, there is no known toxicity and can be safe even if inhaled frequently for the treatment of pulmonary inflammation.

The positive result obtained in this assay is indicative of the anti-inflammatory activity of the compound of formula (I).

Claims (6)

In the manufacture of a medicament for topically reducing inflammation in a mammal suffering from inflammation and for reducing the viscosity of mucus from lung disease patients, including thickened or accumulated mucus secretions, the formula I or all isoforms thereof Use of <Formula I> In the formula, One of X, Y, or Z Indicates Each R represents hydrogen or methyl, The other two of X, Y or Z are each -CO-R ¹ , wherein R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of cyano, halo and C _1-6 straight or branched alkoxy Substituted straight or branched C _11-21 alkyl or C _11-21 alkenyl). The method of claim 1 wherein the phospholipid of formula (II) or all isomeric forms thereof are used. <Formula II> In the formula, Each R represents hydrogen or methyl, R ¹ represents a straight or branched C _11-21 alkyl or C _11-21 alkenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo, C _1-6 straight or branched alkoxy, or cyano. Indicated). The method according to claim 1 or 2, wherein dipalmitoyl or distearoyl phosphatidylcholine is used. The method of claim 1, wherein dipalmitoyl phosphatidylcholine is used. The method according to any one of claims 1 to 4, wherein at least one of the compounds is used for the preparation of a topical medicament for the treatment of diseases selected from the group consisting of asthma, bronchitis, cystic fibrosis, conjunctivitis, dermatitis, hemorrhoids and rhinitis. How to. Use of the following formula (I) or all isomeric forms thereof in the preparation of aerosolized powders or liquid medicaments for reducing the viscosity of mucus from patients with lung disease, including thickened or accumulated mucus secretions. <Formula I> In the formula, One of X, Y, or Z Indicates Each R represents hydrogen or methyl, The other two of X, Y or Z are each -CO-R ¹ , wherein R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of cyano, halo and C _1-6 straight or branched alkoxy Substituted straight or branched C _11-21 alkyl or C _11-21 alkenyl).