An inhalable rapamycin formulation for the treatment of pulmonary hypertension

Inactive Publication Date: 2017-10-26
LAM THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is a safe and effective aerosol formulation of a rapamycin composition that can deliver the drug directly to target tissues in the lung, resulting in higher concentrations of drug in those tissues with minimal toxicity. The formulation has a low systemic exposure to rapamycin and is expected to have an improved safety profile compared to other dosage forms. The invention is especially useful for chronic or prolonged use. The rapamycin composition is delivered as a solution in a pharmaceutically acceptable vehicle and can include various additives to increase its stability, solubility, and / or absorption. The biological activities of the delivered drug indicate that it effectively inhibits mTOR signaling in the target tissues, providing a therapeutic effect with a low dosage and minimal toxicity.

Problems solved by technology

Those disorders include asthma, pneumonia, chronic obstructive pulmonary disease (COPD), left heart failure and / or coronary disease, which make the diagnosis of PH often challenging.
The walls of the smallest blood vessels thicken and are no longer able to transfer oxygen and carbon dioxide normally between the blood and the lungs.
This makes it harder for the heart to pump blood through the lungs.
This further increases the blood pressure within the lungs and impairs blood flow, increases the work load of the heart, and causes hypertrophy of the right ventricle.
The heart is less able to pump blood through the lungs resulting in heart failure and death in patients.
Treatment only relieves symptoms and slows the progress of the disease.
Despite considerable advances in medical therapy for PH, long-term mortality remains high, largely as a result of heart failure and other cardiovascular diseases.
In contrast, these drugs have not been proven effective for people with PH due to an underlying lung disease.
Unfortunately, many patients respond poorly to these therapies or stop responding to them over time.
Although there is some evidence that available therapies have secondary effects on vascular remodeling, there are currently no therapies that target abnormal cell proliferation in PH.
The molecular mechanism of PH is not known, but it is believed that the endothelial dysfunction results in a decrease in the synthesis of endothelium-derived vasodilators such as nitric oxide and prostacyclin.
Rapamycin use in its clinically approved context has several known adverse effects including lung toxicity (the RAPAMUNE label warns that it is not indicated for lung transplant patients), increased cancer risk, and diabetes-like symptoms.
In addition, a 2012 meta-analysis concluded that 10% of cancer patients administered temsirolimus or everolimus may experience mild grade toxicity with a worsening of quality of life and, in some case, interruption of therapy.
But an aerosol formulation of rapamycin for delivery directly to the lungs would be considered highly unlikely to succeed in view of rapamycin's well-known lung toxicity, as exemplified by the articles cited above.
In view of the wide-spread recognition of the potential for rapamycin-induced lung toxicity, a pharmaceutical composition comprising rapamycin for pulmonary delivery was not considered to be a viable therapeutic option in humans.

Method used

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  • An inhalable rapamycin formulation for the treatment of pulmonary hypertension
  • An inhalable rapamycin formulation for the treatment of pulmonary hypertension
  • An inhalable rapamycin formulation for the treatment of pulmonary hypertension

Examples

Experimental program
Comparison scheme
Effect test

example 1

Aqueous Aerosol Formulation

[0199]An exemplary aqueous formulation of rapamycin was prepared using the following components.

ComponentAmount (g)Mass Fraction (w / w)rapamycin0.10.01%  ethanol25025%propylene glycol25025%polysorbate 800.020.002%  water50050%Total1000

[0200]Blending Procedure: in a 1000 ml amber volumetric flask, blend 250 propylene glycol with 250 ethanol until uniform. Then sequentially dissolve first 100 mg rapamycin then 20 mg polysorbate 80 in the propylene glycol and ethanol solution. Add water to bring the volumetric to 1000 ml and stir or sonicate until uniform and all the rapamycin is dissolved. Store at controlled temperature away from light.

example 2

Dry Powder Formulation

[0201]Batch 06RP68.HQ00008 and 06RP68.HQ00009. These two formulations are each a blend of micronized drug (rapamycin) particles dispersed onto the surface of lactose carrier particles. The final composition of each batch comprises 1% (w / w) drug particles having a mean diameter of about 2.60 microns and 3.00 microns, respectively. Drug particles having a suitable size range are made by wet polishing (06RP68.HQ00008) or jet milling (06RP68.HQ00009), as described below. While this example used 1% (w / w) rapamycin, a range 0.5 to 20% is practicable. The carrier particles consist of a blend of two carriers, Respitose® SV003, present at 95.5% (w / w) and having particle sizes of about 30 to 100 microns (equivalent spherical diameter), and Respitose® LH300 (Lactohale 300) present at 5.5% (w / w) and having particle sizes less than 10 microns (equivalent spherical diameter). After blending, the blends were assayed to confirmed homogeneity and drug content of 1%.

[0202]To red...

example 3

Determination of Rapamycin in Lung and Blood Following Administration by Oropharyngeal Aspiration (OPA) and Oral Gavage to C57BL6 Mice

[0204]This study was conducted to evaluate the concentration of rapamycin in male C57BL / 6 mice after administration of rapamycin at a very high target dose of 1 mg / kg by gavage and oropharyngeal aspiration (OPA). A method for the analysis of rapamycin in mouse blood and lung homogenate was developed using liquid chromatography with tandem mass spectrometry detection (LC-MS / MS). Calibration curves of rapamycin using triplicate concentrations were analyzed between 1 ng / mL and 2000 ng / mL in mouse blood, and between 2 ng / mL and 20,000 ng / mL in mouse lung homogenate. Accuracy, precision and linearity were within expected ranges.

[0205]In pilot studies, the efficiency of vehicle delivery to the lungs via oropharyngeal aspiration with a volume of 50 μL per mouse was evaluated by administration of Evans Blue dye. The presence of blue dye only in lungs was veri...

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Abstract

The present invention relates to methods and compositions for the treatment and prophylaxis of pulmonary arterial hypertension (PAH) in a human subject in need of such treatment, the methods comprising the pulmonary administration to the subject, preferably via inhalation of a composition comprising rapamycin or a prodrug or derivative thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present PCT application claims priority to U.S. Provisional Pat. App. Ser. No. 62 / 060,988 filed Oct. 7, 2014 and U.S. Provisional Pat. App. Ser. No. 62 / 144,145 filed on Apr. 7, 2015, the full disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to methods and pharmaceutical compositions for pulmonary delivery by inhalation, the composition comprising rapamycin for the prophylaxis and treatment of pulmonary hypertension.BACKGROUND OF THE INVENTION[0003]Pulmonary hypertension (PH) is an increase of blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to chest pain, dizziness, fainting, fatigue, leg swelling, light-headedness during exercise, shortness of breath during activity and / or weakness. The symptoms of PH are similar to those of other more common heart and lung problems. Those disorders include...

Claims

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Application Information

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IPC IPC(8): A61K31/436A61K9/16A61K9/00A61K9/12A61K45/06
CPCA61K31/436A61K9/0075A61K45/06A61K9/1623A61K9/1617A61K9/12A61J1/00A61M15/0028A61K31/557A61P11/00A61P43/00A61P9/12Y02A50/30A61K2300/00
InventorARMER, THOMASMELVIN, JR., LAWRENCE S.ROTHBERG, JONATHAN M.LICHENSTEIN, HENRI
OwnerLAM THERAPEUTICS