Claims
- 1. A nonphospholipid lipid composition for treatment of interstitial lung diseases consisting essentially of nonphospholipid lipid component and a drug, or its salt or ester, suitable for delivery by inhalation into the deep lung wherein lipid component forms lipid particles.
- 2. The composition of claim 1 wherein the lipid component is a mixture of cholesterol and a cholesterol ester salt and lipid particles are liposomes or micelles.
- 3. The composition of claim 2 wherein the cholesterol ester is selected from the group consisting of sulfate, phosphate, nitrate and maleate and the salt is selected from the group consisting of sodium, potassium, lithium, magnesium and calcium.
- 4. The composition of claim 3 wherein the cholesterol ester salt is sodium cholesterol sulfate.
- 5. The composition of claim 4 wherein the ratio of sodium cholesterol sulfate to cholesterol to the drug is from 30 to 70 mole % of sodium cholesterol sulfate; from 20 to 50 mole % of cholesterol and from 0.01 to 20 mole % of the drug or the salt or ester thereof.
- 6. The composition of claim 5 wherein the ratio is 50:40:10.
- 7. The composition of claim 5 wherein the ratio is 55:40:5.
- 8. The composition of claim 5 wherein the ratio is 53:37:9.
- 9. The composition of claim 6 wherein the drug is selected from the group consisting of aldosterone, beclomethasone, betamethasone, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, dexamethasone, difluorocortolone, fluclorolone, fluorocortisone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluorocortolone, fluorometholone, flurandrenolone, halcinonide, hydrocortisone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, triamcinolone, metaproterenol sulfate, aminophylline, terbutaline, albuterol, theophyline, ephedrine, isoproterenol, bitolterol, pirbuterol, adrenaline, norepinephrine, procaterol, salmeterol, fluoromethasone, medrysone, fluticasone, atropine methyl nitrate, ipratropium bromide, cromolyn sodium, nedocromil, bleomycine, azathioprine, doxorubicin, daunorubicin, cyclophosphomide, vincristine, etoposide, lomustine, cisplatin, procarbazine, methotrexate, mitomycin, vindesine, ifosfamide, altretamine, acyclovir, azidothymidine, ganciclovir, enviroxime, ribavarin, rimantadine, amantadine, penicillin, erythromycin, tetracyclin, cephalothin, cefotaxime, carbenicillin, vancomycin, gentamycin, tobramycin, piperacillin, moxalactam, cefazolin, cefadroxil, cefoxitin, amikacin, amphotericin B, micozanole, apresoline, atenolol, captopril, verapamil, enalapril, dopamine, dextroamphetamine, pentamidine, pyribenzamine, chlorpheniramine, diphenhydramine, interferon, interleukin-2, monoclonal antibodies, gammaglobulin, ACTH, insulin, gonadotropin, dilaudid, demerol, oxymorphone, hydroxyzines, hemophilus influenza vaccine, pneumococcus vaccine, HIV vaccine and respiratory syncitial virus vaccine or their respective pharmaceutically acceptable salts or esters, alone or in combination.
- 10. The composition of claim 9 wherein the drug is beclomethasone dipropionate.
- 11. The composition of claim 10 wherein the composition is aerosolized into particles predominantly smaller than mass median aerodynamic diameter 2..mu..
- 12. The composition of claim 11 wherein beclomethasone dipropionate is present in amount between 0.4 to 2 mg/ml of liposome composition.
- 13. A method of treating interstitial lung diseases by inhalation route of administration to a person in need of such treatment a therapeutically effective amount of nonphospholipid lipid composition consisting essentially of a drug and nonphospholipid lipid components aerosolized into aerosol particles having mass median aerodynamic diameter smaller than 2.1 micron and providing a slow or sustained release of the drug in the lung.
- 14. The method of claim 12 wherein the lipid composition forms liposome or micelle lipid particles comprising 30 to 70 mole % of sodium cholesterol sulfate, 20 to 50 mole % of cholesterol and from 0.01 to 20 mole % of a drug.
- 15. The method of claim 13 wherein the drug is selected from the group consisting of aldosterone, beclomethasone, betamethasone, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, dexamethasone, difluorocortolone, fluclorolone, fluorocortisone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluorocortolone, fluorometholone, flurandrenolone, halcinonide, hydrocortisone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, triamcinolone, metaproterenol sulfate, aminophylline, terbutaline, albuterol, theophyline, ephedrine, isoproterenol, bitolterol, pirbuterol, adrenaline, norepinephrine, procaterol, salmeterol, fluoromethasone, medrysone, fluticasone, atropine methyl nitrate, ipratropium bromide, cromolyn sodium, nedocromil, bleomycine, azathioprine, doxorubicin, daunorubicin, cyclophosphomide, vincristine, etoposide, lomustine, cisplatin, procarbazine, methotrexate, mitomycin, vindesine, ifosfamide, altretamine, acyclovir, azidothymidine, ganciclovir, enviroxime, ribavarin, rimantadine, amantadine, penicillin, erythromycin, tetracyclin, cephalothin, cefotaxime, carbenicillin, vancomycin, gentamycin, tobramycin, piperacillin, moxalactam, cefazolin, cefadroxil, cefoxitin, amikacin, amphotericin B, micozanole, apresoline, atenolol, captopril, verapamil, enalapril, dopamine, dextroamphetamine, pentamidine, pyribenzamine, chlorpheniramine, diphenhydramine, interferon, interleukin-2, monoclonal antibodies, gammaglobulin, ACTH, insulin, gonadotropin, dilaudid, demerol, oxymorphone, hydroxyzines, hemophilus influenza vaccine, pneumococcus vaccine, HIV vaccine and respiratory syncitial virus vaccine or their respective pharmaceutically acceptable salts or esters, alone or in combination.
- 16. The method of claim 14, wherein the composition is 50 mole % of sodium cholesterol sulfate, 40 mole % of cholesterol and 10 mole % of beclomethasone dipropionate.
- 17. The method of claim 14, wherein beclomethasone dipropionate is present in amount from 0.4 to 2 mg/ml of liposome composition.
- 18. An inhalation method for treatment of lung diseases by treating a person in need of such treatment with a therapeutically effective amount of aerosolized liposome composition consisting essentially of a drug and nonphospholipid lipid components aerosolized into particles predominantly smaller than 1 micron mass median aerodynamic diameter by the inhalation route of administration.
- 19. The method of claim 17 wherein the lipid composition forms liposome or micelle particles comprising 30 to 70 mole % of cholesterol sulfate, 20 to 50 mole % of cholesterol and 0.01 to 20 mole % of the drug.
- 20. The method of claim 18 wherein the drug is selected from the group consisting of aldosterone, beclomethasone, betamethasone, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, dexamethasone, difluorocortolone, fluclorolone, fluorocortisone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluorocortolone, fluorometholone, flurandrenolone, halcinonide, hydrocortisone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, triamcinolone, metaproterenol sulfate, aminophylline, terbutaline, albuterol, theophyline, ephedrine, isoproterenol, bitolterol, pirbuterol, adrenaline, norepinephrine, procaterol, salmeterol, fluoromethasone, medrysone, fluticasone, atropine methyl nitrate, ipratropium bromide, cromolyn sodium, nedocromil, bleomycine, azathioprine, doxorubicin, daunorubicin, cyclophosphomide, vincristine, etoposide, lomustine, cisplatin, procarbazine, methotrexate, mitomycin, vindesine, ifosfamide, altretamine, acyclovir, azidothymidine, ganciclovir, enviroxime, ribavarin, rimantadine, amantadine, penicillin, erythromycin, tetracyclin, cephalothin, cefotaxime, carbenicillin, vancomycin, gentamycin, tobramycin, piperacillin, moxalactam, cefazolin, cefadroxil, cefoxitin, amikacin, amphotericin B, micozanole, apresoline, atenolol, captopril, verapamil, enalapril, dopamine, dextroamphetamine, pentamidine, pyribenzamine, chlorpheniramine, diphenhydramine, interferon, interleukin-2, monoclonal antibodies, gammaglobulin, ACTH, insulin, gonadotropin, dilaudid, demerol, oxymorphone, hydroxyzines, hemophilus influenza vaccine, pneumococcus vaccine, HIV vaccine and respiratory syncitial virus vaccine or their respective pharmaceutically acceptable salts or esters, alone or in combination.
- 21. The method of claim 19, wherein the composition is 50 mole % of sodium cholesterol sulfate, 40 mole % of cholesterol and 10 mole % of beclomethasone dipropionate.
- 22. The method of claim 19, wherein beclomethasone is present in amount from 0.4-2 mg/ml.
- 23. A process of preparing a suspension of nebulized aerosol particles of sizes predominantly smaller than 2.1 microns of nonphospholipid lipid particles comprising:
- (a) preparing a nonphospholipid lipid particles having sizes less than 1 micron in an aqueous suspension; and
- (b) nebulizing suspension under conditions which produce aerosol particles of mass median aerodynamic diameter predominantly smaller than 2.1 microns.
- 24. The process of claim 23 wherein the lipid particle is liposome.
- 25. The process of claim 23 wherein the lipid particle is micelle.
- 26. The process of claim 23 wherein the nebulizer is any nebulizer suitable for the generation of particle aerosols predominantly smaller than 2.1 microns mass median aerodynamic diameter.
- 27. A nonphospholipid micelle composition for treatment of interstitial lung diseases consisting essentially of nonphospholipid lipid components and a drug or its salt or ester, suitable for delivery by inhalation into the deep lung.
- 28. A nonphospholipid liposome composition for treatment of interstitial lung diseases consisting essentially of nonphospholipid lipid components and a drug or its salt or ester, suitable for delivery by inhalation into the deep lung wherein liposome sizes are predominantly not larger than 1.0 microns.
BACKGROUND OF THE INVENTION
This is a Continuation-in-Part application of U.S. patent application entitled "A Novel Liposome Composition for Sustained Release of Steroidal Drugs in Lungs", Ser. No. 284,158, filed on Dec. 14, 1988 and which is now a U.S. Pat. No. 4,906,476 issued on Mar. 6, 1990.
1. Field of the Invention
Present invention relates to a novel nonphospholipid liposome composition suitable for treatment of interstitial lung diseases. In particular, the composition provides efficient loading and sustained release of steroidal and other drugs deposited in the deep lung via small size aerosol particles, and is particularly useful in formulating steroids for nebulized inhalation of small aerosol particles.
2. Related Disclosures
Interstitial lung diseases (ILD) are disorders involving lung parenchyma with different etiologies but similar clinical features and diffuse pathologic changes that affect primarily interalveolar interstitial tissue.
Interstitial lung diseases form a heterogeneous group of nearly two hundred diffuse, noninfectious, nonmalignant, inflammatory, and often fatal disorders of the lower respiratory tract, resulting in pathological changes of alveolar tissue, in particular alveolar septum, epithelial and endothelial cells. These diseases progress from the initial acute stage through semichronic to chronic stage and are characterized by progressive development of extensive lung fibrosis or granulomatosis.
In its acute inflammatory phase, interstitial lung diseases are characterized by abnormal accumulation of polymorphonuclear leukocytes, histiocytes, lymphocytes, plasma cells and easinophils with proteinaceous exudate in alveoli and brochioles.
Interstitial lung disorders are caused by a number of agents of various biological origin, such as bacilli, viruses, rickettsiae, mycoplasmas; by agents of physical origin, such as external or internal radiation, oxygen, sulfur dioxide, chlorine or other gases, metal oxide fumes, mercury, toluene, diiosocyanate or other solvent vapors, hydrocarbons, fluorocarbon or chlorocarbon aerosols; by particles such as inorganic dusts, such as asbestos, crystalline silica, silicates, talc, kaolin, aluminum or coal dust; by organic dusts derived from living animal sources such as duck, chicken, bird, or turkey feathers, or mammal fur; or by plant dust such as mushroom, paprika, wheat weevil, wood, coffee and other similar dusts known to cause lung disease. Another source may be various contact chemical agents, such as aspiration of acid, alkali, gastric content or certain therapeutic or diagnostic agents, such as immunosuppressants, chemotherapeutics, antineoplastics, or antibiotics. Am. J. Med., 70:542 (1981).
The acute inflammatory stage usually develops into a subchronic stage characterized by interstitial pneumonia and by initial stages of interstitial pneumonary fibrosis, lymphoid, eosinophilic granuloma, extrinsic allergic alveolitis or sarcoidosis. Hyperplasis of bronchiolar or alveolar epithelium may also be present at this later stage. If the disorder progresses, the exudate may become organized, and necrosis, scarring, and reepithelialization of alveolar septae may take place.
The whole process may ultimately lead to a chronic stage characterized by extensive interstitial fibrosis and, at a later stage of interstitial fibrosis, to a progressive destruction of the lung and formation of cysts, wherein the lungs take on a cystic appearance interspersed with thick bands of fibrotic tissue called honeycomb lung. At this stage, the lung tissue is remodeled and reorganized. The airway alveolar structure is lost and replaced with irregular air spaces with fibrotic walls. Pathol. Annals, 21:27 (1986).
Prognosis of these diseases is very poor. Untreated, most interstitial lung diseases are progressive and may rapidly become fatal. The patients' condition deteriorates due to an irreversible loss of alveolar-capillary units. At that stage, the respiratory function is severely impaired, and the right side of the heart becomes hypertrophic due to its attempt to maintain cardiac output and compensate for a progressive loss of alveoli-vascular bed. This eventually leads to the development of cor pulmonale. All the above ultimately result in general respiratory insufficiency with decreased delivery of oxygen to vital tissues such as heart and brain and in death. Am. J. Med., 70:542 (1981).
Two groups of primarily occurring interstitial lung diseases are idiopathic pulmonary fibrosis (IPF) and sarcoidosis. Both idiopathic pulmonary fibrosis and sarcoidosis are, in the first stage, characterized by alveolitis, inflammation of the lung parenchyma.
The clinical course of idiopathic pulmonary fibrosis (IPF) is illustrated in Chest, 92:148 (1987). As seen from Table 1 on page 149, almost all patients suffering from IPF die because of respiratory insufficiency or cor pulmonale, with about one-third to one-half patients dying in about five years. The pathogenesis, clinical symptoms and histopathology of the interstitial diseases are illustrated in FIG. 1.
The second most common interstitial lung disease is pulmonary sarcoidosis, a multisystem granulomatous disorder of unknown etiology, characterized histologically by epithelioid granuloma tubercules found usually in lymph nodes, lungs, eyes, liver and skin, but may also appear in spleen, bones, joints, muscle, heart and CNS. The granulomatous tubercles may lead to organ fibrosis, skin, ocular, bronchial, pleural or brain lesions and to many metabolic/hematologic disorders.
Both pulmonary fibrosis or sarcoidosis often lead to respiratory or cardiac failure resulting in death or, alternatively, because of the other symptoms and conditions, result in severe impairment of the quality of the patient's life.
The prevalence of IPF in the United States population is around 0.1 to 0.2% and the prevalence of sarcoidosis is about 0.04%. With the life span of the patient suffering from ILD around five years, an efficient cure would be extremely important and advantageous, particularly since the only effective therapy currently available involves massive doses of steroids.
Conventional therapy of ILD includes systemic administration of multidoses of steroids, in particular corticosteroids or glucocorticoids. Most often used therapy for ILD is 40-80 mg/day of prednisone orally for one to two months. To control symptoms in many ILD chronic cases, a follow-up treatment with lower doses (5-15 mg/day) is needed for weeks, years, or indefinitely. Still, favorable responses to such massive doses of steroids are achieved in only 20-60% of patients. (The Merck Manual, 14th Ed., p. 260 and 685 (1982); Clin. Geriatr. Med., 2:385 (1986); J. Resp. Dis., 10:93 (1989). Moreover, as shown below, massive doses of steroids, while beneficial and tolerable for a short period of time, are accompanied by severe side effects and the benefit of long-term treatment with steroids may be lessened by these undesirable side effects.
Steroids, in particular corticosteroids, have powerful effects on immunologic and hormonal processes and are very effective in treating a wide range of inflammatory diseases, such as arthritis, rheumatoid arthritis, allergic reactions, and conditions such as lung inflammation, alveolitis, asthma, pneumonia and other lung diseases.
As with many potent drugs given systemically, the therapeutic benefits of corticosteroids are accompanied by an array of deleterious side effects, such as muscular atrophy, disruption of adrenal-pituitary axis resulting in stunted growth in children, edema, hypertension, osteoporosis, glaucoma, damage to the immune system leading to susceptibility to viral and fungal infections, psychological disorders, and even heart failure.
Attempts to minimize these complications by administering smaller doses daily or larger doses b.i.d were not very successful. For example, daily systemic administration of smaller, insufficient and inadequate doses of steroids for desired therapy necessitated prolonged treatment. On the other hand, an administration of the higher doses of steroids on alternate days led to peaks of the steroid in the blood level followed by the occurrence of side effects. Both prolonged treatment and side effects were found to be highly undesirable.
Some improvements were achieved by administering steroids via routes that diminish the systemic side effects elsewhere in the body, or by formulating them in delivery systems that might improve the benefit-to-toxicity therapeutic ratio. However, because of poor solubility in water, attempts to formulate steroids in appropriate vehicles for targeted therapies have been generally unsuccessful. Previously used methods for steroid formulation have relied either on use of organic solvents or on crystalline suspensions in an aqueous medium, both of which are prone to cause tissue irritation and may be painful or impossible to administer by certain routes.
To avoid severe systemic side effects, steroids used for treatment of pulmonary conditions may be administered by the inhalation route. Steroidal inhalants are preferred to systemically-administered steroids because they reduce, albeit not eliminate, the side effects. Such reduction is observed even when inhalations are repeated to reach daily recommended doses for treatment of specific pulmonary conditions. However, steroids formulated for inhalation seem to be rapidly absorbed in upper respiratory regions, necessitating frequent dosing, which, in turn, heightens systemic side effects. Very little, if any, of the steroid ends up in alveoli of the lower respiratory region, a primary area affected by the inflammation leading to ILD.
Thus it would be desirable to provide an inhalation formulation which would deliver steroid in sustained time release fashion into the lower lung region.
For successful delivery of steroid into alveoli of the lower pulmonary region, it is important to eliminate from the formulation irritants such as chloroflurocarbons, to decrease the number of required doses, and to provide vehicles that allow deposition of steroid in the alveolar region. Such need can only be met by providing aerosol droplet particles with a mass median aerodynamic diameter of 5 approximately 1-2.1.mu. size with a geometric standard deviation (GSD) of 1.mu.. Providing sustained controlled release of the steroid from such aerosol would be an added benefit. With the size requirement as outlined above for particle aerosol droplets, presized liposomes of approximately 0.2.mu. or micelles of particle size of approximately 0.02.mu., can be used for the generation of aerosol particles that can be deposited in the alveoli in significant amount.
The advantage of inhalation administration of steroids over systemic administration can best be illustrated by a potent anti-inflammatory steroid dexamethasone. Doses of dexamethasone administered systemically by i.v. injection typically range between 0.5 to 9 mg/day. Where, however, dexamethasone is administered via inhalation, the one time dose is approximately 0.084 mg and the corresponding effective daily inhalation dose for dexamethasone is from 0.4 to about 1.0 mg/day. PDR: 1311, 1312 and 1315 (1988).
Beclomethasone, a halogenated synthetic analog of cortisol, faces a similar problem. Beclomethasone dipropionate (BDP) is currently used for oral inhalation and as a nasal spray for treatment of bronchial asthma and seasonal and perennial rhinitis. Because beclomethasone dipropionate is poorly soluble in water, it is currently formulated as a microcrystalline suspension in halogenated alkane propellants, PDR:1003 (1988). Such a formulation is completely unsuitable for treatment of ILD.
The advantages gained with using inhalation rather than a systemic route of administration for treatment of pulmonary diseases are, unfortunately, lessened by the necessity of multiple dosing. Such dosing is inconvenient, unpleasant, and may lead to nasal or oral mucosal tissue damage caused by a repeated use of fluorocarbon propellants, solvents, or other additives necessary for nasal or oral inhalation administration.
Moreover, even with the advantages provided by available inhalation sprays, inhalers, or aerosols for administration of steroids, the requirements for an inhalation formulation suitable for treatment of ILD alveolar inflammation are not met. Since the ILD is a disease of lower respiratory tract, the aerosol droplets carrying the steroid should dominantly be of sizes small enough to reach, enter and be deposited in the alveolar compartment and, to avoid multiple dosing while providing a maximum therapeutic benefit, should also provide a sustained-release of the drug in the alveoli.
Thus, it would be advantageous to have available a steroid composition which is able to carry to and release in the deep lung an effective dose of steroid for extended periods of time, using the minimum amount of steroid. By developing an appropriate formulation vehicle for such therapy, the undesirable side effects accompanying steroid therapy of ILD would be diminished.
Because of their poor solubility in aqueous systems, formulating a steroid in an aqueous solvent requires adding solubilizing agents such as ionic surfactants, cholates, polyethylene glycol (PEG), ethanol, and other solubilizers or using micronized suspension of crystalline drug. While, in general, these agents are considered pharmaceutically acceptable excipients, many of them have, particularly when used for inhalation, have undesirable effects. And since some of these agents are the initial cause of ILD in the first place, their use is doubly imprudent. Therefore, steroid formulations not containing such solubilizing agents and having an aerosol droplets small enough to be able to be deposited in the lung alveoli would be advantageous.
As discussed above, typical treatment of ILD is by oral administration of massive doses of steroids such as 40-80 mg of prednisone/day; 3-9 mg of dexamethasone/day; or 4.8-7.2 mg of betamethasone/day (Respiratory Pharmacology Therapeutics, p. 257 (1978). Because of the specific requirements of aerosol droplets of micron or submicron sizes needed for inhalation therapy of the ILD, such therapy has not been until now available. Consequently, the only available data on inhalation therapy are those used for treatment of asthma. A typical daily inhalation dose of dexamethasone for treatment of asthma is 0.75-1 mg/day (PDR, 1312 [1988]). The typical daily inhalation dose of beclomethasone dipropionate for treatment of asthma is 0.25-0.34 mg/day. (PDR, 1315 [1988]).
Several inhalation steroidal products have been introduced recently which are intended for treatment of various pulmonary conditions. For example PULMICORT.RTM., a Freon propelled metered dose (MDI) aerosol of budesonide, delivers 200 ug of steroid per inhalation puff and is available for the treatment of asthma. In limited clinical studies reported in Amer. Rev. Reso. Dis. 41:A349 (1988) and in Eur. Reso. J., 2:218 (1988), it was found that the administration of a daily dose of 1200 or 2400 ug of inhaled budesonide via Nebuhaler.RTM. showed improvement in chronic relapsing Stage II and III pulmonary sarcoidosis. There are two primary disadvantages connected with the PULMICORT treatment. First, to reach a rather high daily dose of 1.2-2.4 mg, multiple dosing is required which is not desirable in case of lung inflammation. Second, MDI is propelled by a fluorocarbon which alone may be an initial stimulus causing the acute alveolitis. Third, the MDI does not provide particles small enough to enter the alveoli without added spacers or other equipment (Eur. J. Reso. Dis., 68:19 [1988 ]).
NASALIDE.RTM., a commercially available nasal spray containing steroid flunisolide is used primarily as a local topical treatment for allergic rhinitis. The dose required for treatment of asthma is between 1-2 mg and can only be lo delivered in 250 ug/puff. Consequently, several doses per day is needed.
Still another steroidal formulation used for treatment of bronchial asthma by nebulization is a suspension of beclomethasone dipropionate in an aqueous medium (BECOTIDE.RTM.). This suspension has only 50 ug/ml of the active ingredient and has very poor, if any, alveolar deposition. Based on maximum formulable BDP (50 ug/ml) in aqueous medium, it does not provide a sufficient therapeutic amount of steroid to treat sarcoidosis or IPF.
Thus it would be highly desirable to have available a steroidal formulation suitable for inhalation which would provide small, substantially homogeneous size particles allowing the steroid to be deposited in the alveoli.
Certain improvements have previously been achieved by encapsulating steroids in conventional liposomes. For example, smaller doses of steroids were found to be effective when administered in liposome-encapsulated form. Also, modest prolongation of effect and restriction of the drug to the site of administration was achieved, and a marginal degree of decreased rate of systemic uptake was accomplished.
Liposomes, lipid based drug carrier vesicles, are composed of nontoxic, biodegradable lipids, in particular phospholipids which act the same as surfactant in the lung. Attempts have been made to prepare liposomes from nonphospholipid components which have the potential to form lipid bilayers (Biochim. Biophys. Acta. 19:227-232 [1982]). Currently, both conventional and nonphospholipid liposomes are rapidly becoming accepted as pharmaceutical agents which improve the therapeutic value of a wide variety of compounds. Liposome drug delivery systems are reviewed in detail in Cancer Res., 43:4730 (1983).
Liposomes generally have been known to improve formulation feasibility for drugs, provide sustained release of drugs, reduce toxicity and side effects, improve the therapeutic ratio, prolong the therapeutic effect after each administration, reduce the need for frequent administration, and reduce the amount of drug needed and/or absorbed by the mucosal or other tissue.
The use of liposomes as a solubilizing agent for steroids in aqueous, nebulized inhalation suspensions essentially eliminates the use of potentially toxic halogenated hydrocarbon propellants and other solvents, and ensures that the drug stays in a stable suspension. Liposome formulation also prevents the lung irritation caused by drug sedimentation and crystallization often encountered with conventional steroidal suspension preparations.
Notwithstanding the above, utilizing conventional liposomes for inhalation formulations still entails some problems. First, there is a little effect of liposomal entrapment on rapid systemic uptake, indicating that even from the liposomes the steroid is rapidly released. Second, because of their poor formulation properties, many useful steroids must be derivatized or modified to be accommodated within the chemical structure of the liposomes for enhanced retention. For example, a 6-18 carbon-chain ester needs to be present in the steroid molecule for optimal lipophilic interaction between the water-insoluble corticosteroid and the lipid membrane.
The necessity for steroid modification is addressed in EPO application 850222.2, which describes increased binding of the steroid to the liposomal membrane by derivatizing said steroid with a hydrophobic anchor, such as a fatty acyl chain. While the binding of derivatized drug to the membrane was shown to be improved, the steroid derivative still did not sufficiently slow the efflux rates of steroid from liposomes. This was due to the fact that the lipid composition of conventional, phospholipid liposomes does not provide a strong enough barrier to slow down the release of the derivatized steroid and to achieve prolonged release.
U.S. Pat. No. 4,693,999 discloses new steroid derivatives obtained by modification of corticosteroids with fatty acid esters which, when incorporated in the lipid portion of liposomes for delivery via inhalation, provide a prolonged steroid retention in the respiratory tract of experimental animals.
Dexamethasone palmitate, a modified synthetic analog of cortisol, incorporated in liposomes was shown to surpass the effectiveness of microcrystalline cortisol acetate injection into arthritic joints of experimental animals. J. Microencapsulation, 4:189-200 (1987). While the formulation provided enhanced therapy against inflammation and diminished the leakage levels of the steroid into systemic circulation, it was not therapeutically suitable because the charged carrier dicetyl phosfhate, necessary for the liposome formulation, is not pharmaceutically acceptable for certain safety reasons.
It will be appreciated that designing and synthesizing new steroid derivatives is inconvenient, costly, slow, laborious, and most importantly, often changes the drug efficacy. Thus, it would be greatly advantageous to provide a liposomal steroid formulation with substantially improved drug retention without the need for drug modification.
Poorly water-soluble steroids are generally also difficult to load into conventional phospholipid liposomes because they tend to crystallize rather than incorporate into the phospholipid liposomal membrane. Thus, they have similar toxicity upon administration as do nonliposomal steroidal suspensions since these synthetic drugs do not have the right stearic fit in the bilayer matrix of liposomes, the drugs rapidly diffuse out in vivo.
Previously disclosed (EP 87309854.5) small particle aerosol liposomes and liposome-drug combinations for medical use tried to circumvent but fell short of the strict size requirement for delivery of steroid into alveoli. With aerosol particle size requirement for deposition in alveoli around 1-2.1 .mu. MMAD, the size of aerosol droplet delivering drug into alveoli must be substantially within that size limit, preferably with the majority of single aerosol droplet about or smaller than 2 .mu. for optimal alveolar deposition. The above cited reference attempted processing a heterogeneous size (1-10 .mu.) population of liposomes into a more homogenous size of small liposomes using an aerosol nebulizer equipped to reduce the size of liposomes. In this manner, the majority of resulting aerosol particles were less than 5 .mu. in diameter with an aerodynamic mass median diameter ranging from about 1-3 microns. Although some of these particles may reach alveoli, a sizable fraction is far too large to be able to enter the small alveoli and consequently, the drug payload in deep lung could be therapeutically insignificant. Also, because of the sizing by aerosolization, the size distribution of these liposomes is unpredictable and the amount of drug deposited in the deep lung cannot be even estimated, not to say predicted, with any degree of certainty.
Previously available conventional liposomal steroidal formulations have shown an uncontrollable and fast release rate. Measurements of systemic uptake from the respiratory tract after inhalation of underivatized steroids formulated in conventional liposomes indicated little or no effect of liposomal entrapment on the release rate. This means that despite the liposome-binding, the drug was still released relatively quickly from the conventional phospholipid liposomes. This may be due to the fact that all synthetic steroids which are lipophilic tend to be released from the lipid membrane faster than water-soluble drugs encapsulated inside the liposomes because of incompatible stearic fit. Biochem. J. 158:473 (1976).
To provide effective treatment for interstitial lung diseases, it would be greatly desirable to develop a pharmaceutically acceptable composition suitable for inhalation administration where the steroids could be formulated without the need of modifying or derivatizing, which at the same time could carry a sufficient amount of steroid and from which the steroid could be released with a controllable and desired rate in nebulized aerosol droplets of small and homogeneous size. The resulting composition would be capable of (a) solubilizing the underivatized steroid, (b) having high-loading ability, (c) prolonging release, (d) extended stability and (e) being deposited in deep lung tissue.
It is the primary object of this invention to provide the liposome-steroid composition wherein the poorly water soluble or insoluble, sedimentation-prone, underivatized or unmodified steroids are successfully sequestered within the membrane of liposomal lipid vesicles of homogeneous and controllable particle size of 0.2-0.5 .mu., having at the same time high encapsulation values, long-term stability, and effective sustained release of the drug. The resulting composition would allow an administration of low doses of steroid thus reducing or eliminating toxicity and systemic side effects while at the same time providing pharmacologically bioavailable doses of steroid in deep lung alveoli. The composition would also be economically advantageous because it would effectively formulate all therapeutically needed steroids without loss occurring during the steroid formulation or during the therapeutical administration.
One aspect of this invention is to provide a nonphospholipid, cholesterol/cholesterol ester salt/steroid liposome formulation for therapeutic delivery of various underivatized and unmodified steroid drug in the liposome vesicles of uniform and controllable particle size in nebulized form into the deep lung tissue.
Other aspect of this invention is to provide a formulation enabling liposome entrapment or encapsulation of underivatized steroids in the liposome vesicles of uniform and controllable particle size suitable for delivery of steroid to alveoli.
Still another aspect of this invention is to provide a liposome formulation with high encapsulation properties for encapsulating water-insoluble steroids or other drugs suitable for aerosolization.
Yet another aspect of this invention is to provide liposome/drug compositions which has lower toxicity, lower side effects, allows the targeting to and release of steroid in a deep lung tissue, removes need for multiple dosing, can be sterilized, and is sufficiently stable in dried form for long-term storage.
Another aspect of this invention is to provide controlled, sustained release in the deep lung of the steroidal drugs or other from the nonconventional liposome/steroid composition.
Still another aspect is to provide a process for making novel nonconventional liposome compositions for controlled release of steroidal or other drugs delivered by nebulization.
Yet another aspect of this invention is to provide the method of treatment of interstitial lung diseases by administering the nebulized liposomal drug composition by oral inhalation.
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Foreign Referenced Citations (4)
| Number |
Date |
Country |
| EP87309854.5 |
Sep 1988 |
EPX |
| WO8806881 |
Sep 1988 |
WOX |
| WO8806882 |
Sep 1988 |
WOX |
| WO8806883 |
Sep 1988 |
WOX |
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| Biochim. Biophsy. Acta 691:227 (1982). |
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
284158 |
Dec 1988 |
|
Patent Grant
5049389
