An Inhalable Rapamycin Formulation for Treating Age-Related Conditions

a technology of rapamycin and inhalation, which is applied in the direction of drug compositions, respiratory disorders, anti-noxious agents, etc., can solve the problems of affecting the quality of life, and increasing cancer risk, so as to reduce the toxicity of rapamycin and the associated drug concentration, inhibit the signaling of mtor, and reduce the effect of toxicity

Inactive Publication Date: 2017-01-19
LAM THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024]The present invention is based, in part, upon the development of a safe and effective aerosol formulation of a rapamycin composition that is capable of delivering amounts of the rapamycin composition to target tissues effective to exert potent biological activity in those target tissues while minimizing rapamycin associated toxicity. In addition, the invention exploits the discovery of the surprising pharmacokinetics of a rapamycin composition formulated as described herein. As discussed in more detail infra, the rapamycin composition delivered directly to the lungs produced markedly higher concentrations of drug in the lung tissue. The amount of drug in lung tissue was unexpectedly higher than what was predictable from previous oral and intravenous studies. And surprisingly, even relatively high amounts of rapamycin delivered directly to the lungs did not result in toxicity to the lung tissue. Moreover, the amount of drug in lung tissue achieved by the methods described here is demonstrated to be effective to exert potent biological activities including inhibition of cell growth and viability as well as inhibition of S6 phosphorylation in the target tissue. These biological activities indicate that the delivered dose of the rapamycin composition according to the claimed methods is sufficient to inhibit mTOR signaling in the target tissues. Thus, these results demonstrate that the aerosol formulations described here are capable of delivering a low, yet therapeutically effective, dose of rapamycin providing for very low systemic exposure to the drug combined with high efficacy. The result is a markedly improved therapeutic index for rapamycin when administered according to the present invention.

Problems solved by technology

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.
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.
The '569 application does not provide any animal data in support of its methods of treating or preventing an age-related disease, condition, or disorder.

Method used

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  • An Inhalable Rapamycin Formulation for Treating Age-Related Conditions
  • An Inhalable Rapamycin Formulation for Treating Age-Related Conditions
  • An Inhalable Rapamycin Formulation for Treating Age-Related Conditions

Examples

Experimental program
Comparison scheme
Effect test

example 1

Aqueous Aerosol Formulation

[0195]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

[0196]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

[0197]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%.

[0198]To red...

example 3

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

[0201]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.

[0202]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 anti-aging therapy and for the treatment and prophylaxis of age-related diseases and disorders in a human subject in need of such therapy or treatment, the methods comprising the pulmonary administration to the subject, preferably via inhalation, of composition comprising rapamycin, or a prodrug or derivative thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The current application claims priority under 35 U.S.C. §119(e) to provisional application Ser. No. 61 / 975,127 filed Apr. 4, 2014, the disclosure of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to methods and pharmaceutical compositions for pulmonary delivery by inhalation, the compositions comprising rapamycin for anti-aging and for the prophylaxis and treatment of age-related conditions, diseases, and disorders.BACKGROUND OF THE INVENTION[0003]Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus. See e.g., U.S. Pat. No. 3,929,992. Rapamycin is an inhibitor of mTOR. The immunosuppressive and anti-inflammatory properties of rapamycin initially indicated its use in the transplantation field and in the treatment of autoimmune diseases. For example, it was shown to prevent the formation of humoral (IgE-like) antibodies in response to an albu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K31/436
CPCA61K31/436A61K9/0075A61K9/145A61K45/06A61P11/00A61P35/00A61P39/06A61P43/00A61K9/0053A61K9/14A61K47/12A61K47/24A61K47/26
Inventor ARMER, THOMASMELVIN, LAWRENCE S.ROTHBERG, JONATHAN M.LICHENSTEIN, HENRI
Owner LAM THERAPEUTICS
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