WO2001015777A1

WO2001015777A1 - Pulmonary-administration of mineral ascorbates

Info

Publication number: WO2001015777A1
Application number: PCT/US1999/019977
Authority: WO
Inventors: Jeffrey Zidichouski
Original assignee: Oxycal Laboratories Inc
Current assignee: Oxycal Laboratories Inc
Priority date: 1999-08-31
Filing date: 1999-08-31
Publication date: 2001-03-08
Anticipated expiration: 2002-02-28
Also published as: WO2001015777A8; AU5797899A

Abstract

Compositions and methods for pulmonary inhalation treatment. The composition includes a pharmaceutically acceptable mineral ascorbate and, optionally, one or more vitamin C metabolites.

Description

PULMONARY-ADMINISTRATION OF MINERAL ASCORBATES

Technical Field

This invention relates to pulmonary-administration treatment methods and compositions.

More particularly, the invention concerns compositions containing pharmaceutically acceptable mineral ascorbates which are specially adapted for pulmonary administration.

In one respect the invention pertains to treatment methods for applying mineral ascorbates to deep lung tissue surfaces by pulmonary administration.

In another respect, the invention pertains to treatment methods for applying mineral ascorbate to deep lung tissue surfaces by forming an inhalable aerosol of solid mineral ascorbate particles. In another respect the invention pertains to treatment methods for applying mineral ascorbates to deep lung tissue surfaces by forming an inhalable aerosol of liquid particles containing mineral ascorbates.

Definitions

As used herein, the following terms have the meanings indicated below:

"Aerosol" means both a true colloidal dispersion of solid or liquid particles in a gaseous carrier and other dispersions or "sprays", in which the solid or liquid particles are temporarily suspended in the carrier, even though the suspension is not a true colloid.

"Treatment" means prophylaxis, amelioration, prevention or cure of body conditions.

"Pulmonary administration" means any mode of administration which delivers a mineral ascorbate to any surface of the lung, including both inhalation and endotracheal administration, as a liquid, a powder or an aerosol, for local action on pulmonary tissues and/or via pulmonary tissues into the circulatory system for systemic action by the mineral and/or ascorbate moieties.

"Lung surface" means any of the interior surfaces of the lungs, including alveolar surfaces, bronchiolar surfaces and passage between any of these surfaces, either directly for local action on pulmonary tissues or via pulmonary tissues into the circulatory system for systemic action.

Technical Background

Oral administration of a drug may be inefficient to deliver the drug to the intended treatment site in the body. For example, for orally-ingested ascorbic acid to appear in lung tissue and fluids, there must be adequate gastrointestinal absorption, re-distribution, minimal uptake by other tissues and blood cells, minimal influences by first-pass metabolism in the liver and by excretion and, finally, adequate delivery by the circulatory system to the lung tissues.

Although various investigations have attempted to examine the effects of oral vitamin C supplementation on lung function or to reduce the oxidative potential of certain gases, oral ingestion of vitamin C represents a nonspecific and less than ideal drug delivery technique to achieve an increased ascorbic acid content at the lung-air exchange interface, as many clinical or preclinical studies involving oral supplementation failed to show a statistically significant benefit.

IV infusion of ascorbic acid has been employed in limited clinical settings, but long-term chronic administration is not a practical way to improve lung function.

Ascorbic acid has been topically applied to the skin by so-called "transdermal patch" techniques to reduce the appearance of wrinkles. However, it is doubtful that vitamin C in this form would penetrate the stratum corneum in sufficient quantity to gain access to the circulation, and it is more likely that it would cause a high degree of skin irritation before the barrier is penetrated.

Prior Art

Benson et al., U.S. Patent 5,006,343. disclosed pulmonary administration of "a wide range of pharmaceutically active substances" in a liposome-alveolar surfactant protein carrier, for both systemic delivery or local delivery. The disclosed pharmaceutically active substances included "anti-oxidants such as vitamin E, vitamin C, superoxide dismutase and catalase" for "treatment of oxygen toxicity", although the only working example of an antioxidant was vitamin E.

Lichtenberqer, U.S. Patent 5,260,284, disclosed use of "vitamin C" to prevent oxidation of lipid compositions used as an artificial lung surface surfactant, which was administered by infusing a liquid or powder into the endotracheal tube followed by blowing 100% oxygen into the lungs with an anesthetic bag. Likewise, Eqberq, US Patent 5,747 ,533 disclosed that inhalation aerosols can contain "vitamin C" as an antioxidant to protect the active ingredient of the aerosol (unsaturated fatty acids) for treatment of disseminated intravascular coagulation, from oxidation.

Brvce-Smith, US Patent 5,688,532, disclosed that zinc- containing compositions, which were "sprayed" into the nostrils or the eyes to control allergic reactions, may contain vitamin C, or other medicines suitable for nasal or opthalmic administration. Likewise, Deihl, U.S. Patent 4,525,341, disclosed vitamin C-containing aerosols, introduced into the nose or mouth for absorption through the oral or nasal mucous membranes and/or swallowing.

Brief Description of the Invention

I have now discovered that the beneficial effects of vitamin C at the lung-air exchange interface of lung tissue are realized by a treatment method in which the vitamin C component of a composition directly applied to the lung tissue is a pharmaceutically acceptable mineral ascorbate.

According to a presently preferred embodiment of the invention the mineral ascorbate is a pharmaceutically acceptable alkaline earth metal ascorbate, preferably calcium ascorbate or magnesium ascorbate, a pharmaceutically acceptable transition metal ascorbate such as zinc ascorbate or an alkali metal ascorbate, preferably sodium ascorbate or potassium ascorbate.

According to another aspect, the invention contemplates compositions for inhalation application to the lung-air interface of lung tissue, these compositions comprising an inhalable aerosol comprising a pharmaceutically acceptable carrier gas as the continuous phase and a disperse phase of solid particles of the mineral ascorbate.

According to another embodiment of the invention, the compositions for inhalation application comprise an inhalable aerosol comprising a pharmaceutically acceptable carrier gas as the continuous phase and a disperse phase comprising liquid particles containing a mineral ascorbate.

In another embodiment of the invention, I provide a method for applying a mineral ascorbate directly to the lung-air exchange surface of lung tissue, comprising the steps of forming a composition comprising particulate mineral ascorbate, including particles thereof in the range of from about 0.5 to about 10 microns, aerosolizing this composition with a pharmaceutically acceptable gaseous carrier and applying the aerosolized composition to the lung-air exchange surface of lung tissue.

In another embodiment of the invention, I provide a method for applying a mineral ascorbate directly to the lung-air exchange surface of lung tissue, comprising the steps of forming a liquid composition which includes a mineral ascorbate in a pharmaceutically acceptable liquid carrier, aerosolizing this composition with a pharmaceutically acceptable gaseous carrier and applying the aerosolized composition to the lung-air exchange surface of lung tissue. In still another embodiment of the invention, the solid or liquid component of the aerosol compositions and methods of the invention comprises a mineral ascorbate and a metabolite of vitamin C, preferably metabolites which are members of the group consisting of aldonic acids and the pharmaceutically acceptable salts, aldonolactones and aldonolactides thereof, dehydroascorbic acid, threose, erythreose, 4-hydroxy-5-methyl-3(2H)-furanone, 3- hydroxykojic acid and 5-hydroxymaltol. The metabolite is preferably a calcium, magnesium, zinc, sodium or potassium salt of threonic acid, lyxonic acid or xyIonic acid and mixtures thereof.

In yet another embodiment of the invention, I provide an improved method of application of vitamin C to the body, including the heart, including the aortic arch, coronary arteries and arterioles, comprising direct application of a mineral ascorbate to lung tissue, absorption into the blood at the lung-air exchange interface of lung tissue, transport directly to the left atrium of the heart via the pulmonary veins and distribution to other body tissues via the arteriole blood supply.

In still another and further embodiment of the invention, I provide compositions and methods of application thereof to body tissues, comprising aerosols which include the above-described vitamin C metabolites and another therapeutically active component (other than vitamin C), in which the metabolites aid in transport of the other active component across the lung-air exchange interface.

Detailed Description of the Invention

A wide variety of lung-specific conditions are amenable to treatment in accordance with the invention, including infant and adult respiratory distress syndrome ("ARDS", arising from diminished lung surfactant properties), age- related decrease in lung function (caused by age-dependent reduction in lung tissue elasticity and likely related to collagen/elastin levels in the lung), viral pneumonia, bacterial pneumonia, Group B streptococcal infections, oxygen toxicity, alpha-1-anti-protease deficiency, emphysema, asthma (including exercise-induced asthma and cold-induced asthma), the deleterious effects of smoking, tuberculosis, lung cancer, bronchitis, cystic fibrosis, mucopurulent and purulent exacerbation of simple mucoid bronchitis, bronchorrhea, bronchopneumonia, purulent pneumonia, pneumonic-alveolar-consolidation, bronchiectasis, bronchocoele, post-transplantation obliterative bronchiolitis and allergenic brochiolitis (fibrosing alveolitus), and chronic obstructive pulmonary disease ("COPD", a chronic bronchitis/emphysema condition) depending on other specific therapeutically active component(s) included in the treatment compositions. In addition, the compositions and methods of the invention are effectively employed as a pre-treatment to hyperbaric oxygen therapy (HPT) in which the patient breathes pure oxygen at 3-4 atmospheres pressure, a combination which ineluctably generates high levels of damaging free radicals in the lungs .

In addition to mineral ascorbates, other active components of the aerosol compositions of the invention may include, but are not limited to antivirals, such as acyclovir, zidovudine and ribavarin, antibacterials, such as sulfamethoxazole and nalidixic acid, fungicides, such as fungizone and mycostatin, antibiotics such as cephalosporins, penicillin, tetracyclines and aminoglycosides, protease inhibitors such as alpha-1- antiprotease, antioxidants such as vitamin C (in the form of ascorbic acid, to standardize the vitamin C content or pH balance of the final formulation), vitamin E and glutathione, superoxide dismutase and catalase, anti- inflammatory agents such as prostaglandins, salicylates, pyrazolons, propionic acid derivatives and para-aminophenol derivatives, anti-allergenics such as antihistamines, including terfenadine, diphenhydramine, chloropheniramine and promethazine, methyl xanthines such as theophylline and β-adrenergic agonists, sympathomimetic amines, such as epinephrine, phenylephrine, pseudoephedrine, isoproterenol and albuterols, mucolytics such as acetyl cysteine, corticosteroids, such as dexamethasone and triamcinolone and chemotherapeutic agents. The mineral ascorbates used in the practice of my invention are substantially pH neutral, thus avoiding problems which are caused by the introduction of highly acidic forms of vitamin C, such as ascorbic acid. Moreover, the invention takes advantage of the presence of the metal (or cation) moieties of mineral ascorbates which, by themselves, have significant treatment effects. For example, zinc ascorbate advantageously provides biologically active zinc values to lung tissue having rhinoviricidal activity, in addition to the benefits of the ascorbate moiety having vitamin C activity. Similarly, magnesium ascorbate advantageously provides biologically active magnesium values to lung tissues, with resulting pulmonary benefits.

The advantages of pulmonary administration of mineral ascorbates are also realized in the provision of ascorbate for systemic action, yielding significantly higher plasma ascorbate levels with lower dose rates, which is of significant value to patients who have low ascorbic acid tolerance because of gastrointestinal complications. Similarly, the pulmonary administration of potassium ascorbate provides a convenient way of introducing biologically active potassium values for systemic effects.

Inclusion of vitamin C metabolites in the treatment compositions which are introduced by pulmonary administration in accordance with my invention provides faster absorption and longer retention of vitamin C and/or other therapeutically active agents which are normally eliminated via the renal tubular secretion pathway for organic anions, which have an acidic functional group and a pKa<6, as more fully discussed in co-owned U.S. Patent No. 5,070,085, incorporated herein by reference. These beneficial effects of faster absorption and increased retention of therapeutically active components are obtained whether or not the compositions also contain mineral ascorbates. According to this embodiment of the invention the vitamin C metabolites are present in the compositions of the invention in an amount effective to increase the absorption rate and/or retention time of the therapeutically active compound which can be from about 0.1 to about 24 wt.% of the metabolite-therapeutic agent composition, preferably in the range of about 1 to about 7 wt . % .

The treatment compositions of the invention which can be introduced into the body by pulmonary administration are in the form of solid or liquid particles suspended or carried in a pharmaceutically acceptable carrier gas, illustratively, air, carbon dioxide, nitrogen or other carrier gases known in the art, such as dichlorodifluoromethane. To increase the depth of application in the lungs, it is preferred that a predominant portion of these particles be in the size range of from about 0.5 to about 10 microns. Suitable dispensing apparatus for metered pulmonary administration of solids or liquids suspended in a carrier gas are well known and are effectively employed in the practice of my invention. For example, see U.S. Patents 2,992,645 to Fowler, 3,012,555 to Meshberg, 3,219,533 to Mullins, 3,236,458 to Ramis and 3,897,779 to Hansen. Suitable adjuvants for improving the stability of such suspensions are also well known and effective in the practice of my invention, for example, anhydrous ethanol, sorbitan trioleate and the like. Sonication of the suspensions and lyophylization of the particles also improves the stability of these suspensions.

In a presently preferred embodiment of the invention, the aerosolized solid particles comprise a mineral ascorbate, e.g., calcium ascorbate, magnesium ascorbate, sodium ascorbate, potassium ascorbate or zinc ascorbate and mixtures thereof and vitamin C metabolites such as aldonic acids and the pharmaceutically acceptable salts, aldonolactones and aldonolactides thereof, preferably a calcium, magnesium, zinc, sodium or potassium salt of threonic acid, lyxonic acid or xyIonic acid and mixtures thereof. Such solid compositions of mineral ascorbates and vitamin C metabolites are commercially available products sold under the registered trademark "Ester-C®" by Inter-Cal Corporation, Prescott, Arizona, U.S.A. In a further presently preferred embodiment of the invention, the aerosolized liquid particles are formed of a shelf-stable liquid composition containing these mineral ascorbates and vitamin C metabolites. These liquid compositions are commercially available as products sold under the registered trademark "Ester-C®" Topical Concentrate from Inter-Cal Corporation of Prescott, Arizona, U.S.A. These shelf-stable liquid vitamin C concentrates are further described in co- owned pending International Applications PCT/US98/02333, filed February 6, 1998 and PCT/US99/02735, filed February 5, 1999, incorporated herein by reference.

ILLUSTRATIVE WORKING EXAMPLES

The following examples are provided to illustrate to those skilled in the art, how to practice the invention and to more completely describe the presently preferred embodiments thereof. These examples are not intended as limitations on the scope of the invention, which is defined only by the appended claims.

EXAMPLE 1

This example illustrates the preparation of the presently preferred dry powder compositions of the invention, which solid particles are delivered via the use of a dry powder inhaler device. All proportions are stated as a percent by weight.

10 gms of powdered calcium ascorbate composition containing 1% calcium threonate, commercially available as Ester-C®, is fed into a grinding apparatus. This material is ground for about 5 minutes, until 80% of the particles are less than 10 microns in diameter. The composition is screened to remove particles that are in excess of 10 microns in diameter. The resulting material is loaded in sealed gelatin, plastic or other capsules and inserted into a suitable, commercially available dry powder inhaler device, for example devices like or similar to an Aerolizer™, a Turbuhaler™, a Spinhaler™ or a Rotohaler™. ithin the device, a mechanical mechanism is activated to puncture the capsule which contains 200 mgs of the above composition. Next, the device is then placed into the mouth and the patient slowly and deeply breathes through the device and so as to suspend the dry powder contained in the capsule and inhales the composition thus providing delivery of the air-suspended particles to the respiratory tract.

Example 2

This example illustrates the preparation of a mineral ascorbate dry powder composition containing an additional therapeutic agent for the treatment of asthma.

400 milligrams of beclomethasone dipropionate powder, screened to remove particles that are greater than 10 microns in diameter, is added to 9.6 g of the ground calcium ascorbate-threonate composition of Example 1 and the resultant composition is mixed for 5 minutes to yield a uniformly mixed composition. The resultant ground material, comprised of calcium ascorbate, calcium threonate, and beclomethasone dipropionate, is loaded into gelatin, plastic or other capsules and delivered to the respiratory tract using a dry powder inhaler device as indicated in Example 1. The configuration of the inhaler device is adjusted to deliver the desired dose of beclomethasone for each actuation of the inhaler. Example 3

This example illustrates the preparation of the presently preferred aerosol compositions of the invention, which solid particles are suspended in a carrier gas. All proportions are stated as a percent by weight.

10 gms of powdered calcium ascorbate composition containing 1% calcium threonate, commercially available as Ester-C®, is fed into a grinding apparatus and the material is ground for about 5 minutes, until 80% of the particles are less than 10 microns in diameter and the composition is screened to remove particles that are in excess of 10 microns, the resulting material that passes through the screen is mixed for 3 minutes to yield a uniformly mixed composition and then loaded into a commercially available pressurized pulmonary dispenser, also known as a metered dose inhaler (MDI). The MDI is designed to deliver a dose of 200 mgs of aerosolized particles suspended in chlorofluorocarbon propellants such as CFC-11 or CFC-12 or non-chlorofluorocarbon propellants known as fluorocarbons such as HFC131A or HFC-227 per activation.

Example 4

This example illustrates the preparation of a mineral ascorbate aerosol composition containing an additional therapeutic agent for the treatment of asthma.

400 milligrams of beclomethasone dipropionate powder is screened to remove particles that are greater than 10 microns in diameter. The screened powder is added to 9.8 gms of the ground and screened calcium ascorbate/calcium threonate composition of Example 1 and the resultant composition is mixed for 5 minutes to yield a uniformly mixed composition. The resultant blended material of calcium ascorbate, calcium threonate, and beclomethasone dipropionate is loaded into the pulmonary dispenser of Example 3 and pressurized with an appropriate carrier gas/propellant as described in Example 3. The dispenser's orifice and the activation mechanism are sized to deliver 200.4 mgs of the ground powder composition as an inhalable suspension in the carrier gas such that 400μg of beclomethasone dipropionate and 200 mgs of Ester-C® dry powder are delivered upon the activation of the device.

Example 5

This example illustrates the preparation of a nebulizing solution or an aerosol composition of liquid mineral ascorbate solution useful in the practice or other presently preferred embodiments of the invention.

5 mL of liquid mineral ascorbate solution containing 14% vitamin C and 0.14% calcium threonate dissolved in a polyglycol solution, disclosed in the Oxycal Laboratories Patent Application PCT/US99/02735 and commercially available as Ester-C® Topical Concentrate, is placed in a plastic nebulizer container from which a patient would inhale from the device to provide delivery of the atomized liquid mineral ascorbate to the respiratory tract. Alternatively, 1-5 mL of the 14% vitamin C/0.14% calcium threonate solution could also be inhaled to effect its delivery to respiratory tract using a pump-activated spray bottle or atomizer. Example 6

This example illustrates the preparation of a nebulizing solution or an aerosol composition of a liquid mineral ascorbate composition containing an additional therapeutic agent for the treatment of asthma.

2 mL of liquid mineral ascorbate solution containing 14% vitamin C and 0.14% calcium threonate and 10 mg of Sodium Chromolyn dissolved in a polyglycol solution, disclosed in the Oxycal Laboratories Patent Application No. PCT/US99/02735 and commercially available as Ester-C® Topical Concentrate, is placed in a plastic nebulizer container from which a patient would inhale from the device to provide the delivery of the atomized liquid mineral ascorbate (140 mg ascorbate) and 10 mg of Sodium Chromolyn to the respiratory tract.

Example 7

This example illustrates other dry powder compositions useful in the practice of the invention.

Example 8

Powdered mineral ascorbates are substituted in whole or in part for lactose or glucose powders as diluent-carriers in MDI and in other dry powder drug formulations containing drugs, e.g., Beta-agonists used in pulmonary therapy, in which the dose per activation of the inhaler dispenser is very small, e.g., in the range of 5-20 micrograms per activation. Such formulations provide the therapeutic benefit of the introduction of the pH neutral form of vitamin C in addition to the delivery of the other drug(s) carried by the mineral ascorbate.

Example 9

This example illustrates the use in adult patients of the compositions of Examples 1-7.

Up to 6 doses per day of the dry powder composition of Example 1 are self-administered by an adult patient diagnosed with chronic pulmonary distress syndrome. Within 21 days symptoms of chronic pulmonary distress syndrome of the patient will be reduced.

Up to 6 doses per day of the dry powder composition of Example 2 are self-administered by an adult patient diagnosed with asthma. Within 21 days symptoms of asthma of the patient will be reduced.

Up to 6 metered doses per day of the aerosol composition of Example 4 are self administered by an adult patient diagnosed with chronic pulmonary distress syndrome. Within 21 days symptoms of chronic pulmonary distress syndrome of the patient will be reduced. Up to 6 doses per day of the nebulizing composition of Example 5 are self administered by an adult patient diagnosed with chronic pulmonary distress syndrome. Within 21 days symptoms of the patient will be reduced.

Up to 6 doses per day of the dry powder composition of Example 7A-70 are self administered by an adult patient diagnosed with chronic pulmonary distress syndrome. Within 21 days symptoms of chronic pulmonary distress syndrome of the patient will be reduced.

Having described my invention in such clear, concise and exact terms as to enable persons skilled in the art to which it pertains to understand and practice it, and, having disclosed the presently preferred embodiments thereof, I CLAIM:

Claims

1. In a treatment method, including the step of applying a composition containing a vitamin C component to the lung-air exchange surface of lung tissue, the improvement wherein said Vitamin C component comprises a pharmaceutically acceptable mineral ascorbate.

2. The method of Claim 1, wherein said mineral ascorbate is a pharmaceutically acceptable alkaline earth metal ascorbate.

3. The method of Claim 2 , wherein said alkaline earth metal ascorbate is magnesium ascorbate.

4. The method of Claim 2, wherein said alkaline earth metal ascorbate is calcium ascorbate.

5. The method of Claim 1, wherein said mineral ascorbate is a pharmaceutically acceptable transition metal ascorbate.

6. The method of Claim 5, wherein said transition metal ascorbate is zinc ascorbate.

7. The method of Claim 1, wherein said mineral ascorbate is a pharmaceutically acceptable alkali metal ascorbate.

8. The method of Claim 7, wherein said alkali metal ascorbate is sodium ascorbate.

9. The method of Claim 7 , wherein said alkali metal ascorbate is potassium ascorbate.

10. A composition adapted for inhalation application to the lung-air interface of lung tissue, said composition comprising an inhalable aerosol including solid particles of a pharmaceutically acceptable mineral ascorbate.

11. A composition adapted for inhalation application to the lung-air exchange interface of lung tissue, said composition comprising an inhalable aerosol of liquid particles containing a pharmaceutically acceptable mineral ascorbate suspended in a pharmaceutically acceptable carrier gas.

12. A method for applying a mineral ascorbate to the lung-air exchange surface of lung tissue, comprising the steps of:

(a) forming a composition comprising a pharmaceutically acceptable particulate mineral ascorbate, including particles thereof in the range of from about 0.5 to about 10 microns;

(b) aerosolizing said composition with a pharmaceutically acceptable gaseous carrier; and

(c) applying said aerosolized composition to the lung- air exchange surface of lung tissue by inhalation.

13. A method for applying a mineral ascorbate to the lung-air exchange surface of lung tissue, comprising the steps of:

(a) forming a liquid composition comprising a pharmaceutically acceptable mineral ascorbate in a pharmaceutically acceptable liquid carrier;

(b) aerosolizing said liquid composition with a pharmaceutically acceptable gaseous carrier; and

(c) applying said aerosolized liquid composition to lung tissue by inhalation.

14. The composition of Claim 10, which further includes a vitamin C metabolite.

15. The composition of Claim 11, which further includes a vitamin C metabolite.

16. The composition of Claim 14, in which said metabolite is a member of the group consisting of

(a) aldonic acids and the pharmaceutically acceptable salts, aldonolactones and aldonolactides thereof; and

(b) dehydroascorbic acid, threose, erythreose, 4- hydroxy-5-methyl-3(2H)-furanone, 3-hydroxy kojic acid and 5-hydroxymaltol.

17. The composition of Claim 15, in which said metabolite is a member of the group consisting of