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Method for reducing side effects from administration of phosphodiesterase-4 inhibitors

a phosphodiesterase and inhibitor technology, applied in the field of topical medications, can solve the problems of high incidence of diarrhea, nausea and abdominal pain, sharp spike in plasma concentration, etc., and achieve the effect of reducing gastrointestinal side effects, reducing cmax spike, and producing high au

Inactive Publication Date: 2020-05-21
ARCUTIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a new discovery that adding phosphate ester surfactants to a formula containing a PDE-4 inhibitor can reduce jerk movements in the body, which results in better patient compliance while also reducing gastrointestinal side effects.

Problems solved by technology

Although these drugs are clinically useful, their use has been limited at times due to the high incidence of side effects including diarrhea, weight loss, nausea, headache, back pain, insomnia, dizziness, flu-like symptoms and decreased appetite, that are associated with their administration.
However, the prescribing information for DAXAS® does report a high incidence of diarrhea, nausea, and abdominal pain associated with this medication.
When roflumilast is orally administered, the drug is rapidly absorbed, resulting in a sharp spike in plasma concentration.
This results in an episodic variation in blood levels of drug and continued gastrointestinal side effects due to the renewed high spike Cmax levels following each administration of the drug.
Although Bolle does not discuss the incidence of side effects that occur following topical administration of the roflumilast formulations, because Cmax with the topical formulations, irrespective of the composition of the topical formulation, is similar to that which is obtained with orally administered formulations, and because side effects are correlated with Cmax, it would be expected that administration of any of the topical formulations, irrespective of composition, would cause an incidence of side effects similar to that caused by orally administered formulations.
This low aqueous solubility has been problematic for the development of parenteral preparations and topical emulsions, suspensions, gels or solutions containing water.

Method used

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  • Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
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  • Method for reducing side effects from administration of phosphodiesterase-4 inhibitors

Examples

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example 1

ons According to the Invention and of the Prior Art

[0072]A first formulation of the invention, hereafter referred to as Formulation 1, was made by combining roflumilast with a phosphate ester surfactant and water. The formulation was buffered with NaOH to obtain a pH of 6.5.

[0073]A second formulation of the invention, hereafter referred to as Formulation 2, was made by combining the above constituents and adding diethylene glycol monoethyl ether. This formulation was buffered with NaOH to obtain a pH of 6.5.

[0074]A formulation that is not of the invention, hereafter referred to as Comparative Formulation 3, was made by combining roflumilast with diethylene glycol monoethyl ether. This formulation was gelled with hydroxylpropyl cellulose so that it would have a similar viscosity and spread on the skin like the two phosphate ester surfactant emulsion Formulations 1, and 2. This semisolid formulation was likewise buffered with NaOH to obtain a pH of 6.5.

[0075]The compositions of these ...

example 2

se Testing of Formulations of Example 1

[0076]Male and female swine (Gottingen Minipig® breed) (Marshall BioResources, North Rose, N.Y.) were ordered to weigh 8 to 12 kg at arrival. On the day prior to administration of one of the topical cream semisolid formulations of Example 1 containing 0.15% roflumilast, the hair was clipped from the back of each animal. The pigs were sedated for the shaving procedure. Care was taken to avoid abrading the skin.

[0077]Two (2) grams of one of the cream formulations of Example 1 for each kg of pig weight was distributed over the clipped skin area by gentle inunction with a glass stirring rod or stainless-steel spatula. The cream formulation was applied evenly with a thin, uniform film beginning at the scapular region and moving caudally over the test site. The width of the test site area was bilaterally divided by the spine. Six pigs (3 males and 3 females) were administered a single dose of the Formulation 2. Blood was sampled from the anterior ven...

example 3

on of the Invention and a Formulation of the Closest Prior Art

[0080]A third embodiment of the invention, hereafter referred to as Formulation 4, was made by combining roflumilast at a concentration of 0.3% w / w with a phosphate ester surfactant and water. The formulation was buffered with NaOH to obtain a pH of 5.5. This formulation is similar to Formulation 1 except that the concentration of roflumilast is 0.3% rather than 0.15% and the emulsion is buffered to a pH value of 5.5 rather than a pH value of 6.5.

[0081]A formulation that is not of the invention, hereafter referred to as Comparative Formulation 5, was made by combining roflumilast at a concentration of 0.3% containing a phosphate ester surfactant, a polyoxyl stearyl ether surfactant and diethylene glycol monoethyl ether, as well as other excipients. This formulation is a cream formulation containing a frequently used phosphate ester surfactant that is not Crodafos CES.

[0082]A formulation that is not of the invention, herea...

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Abstract

A method for altering the PK profile of a pharmaceutical formulation containing a PDE-4 inhibitor, such as roflumilast, to reduce the spike in Cmax. The spike in Cmax is reduced by topically administering the PDE-4 inhibitor in combination with one or more phosphate ester surfactants. Reducing the spike in Cmax will reduce gastrointestinal side effects and result in better patient compliance.

Description

CROSS REFERENCE OF RELATED APPLICATION[0001]This application claims the benefit under 35 U.S.C. § 119(e) of the filing date of provisional patent application Ser. No. 62 / 768,314 filed Nov. 16, 2018, the disclosure of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention pertains to the field of topical medications for the treatment of medical disorders. In particular, the invention pertains to topical formulations containing an active pharmaceutical ingredient that is an inhibitor of the enzyme phosphodiesterase-4. The formulations are pharmaceutically efficacious but have decreased gastrointestinal side effects.BACKGROUND OF THE INVENTION[0003]Drugs that inhibit the enzyme phosphodiesterase-4 (PDE-4) have been found to be useful in the medical treatment of many medical conditions, most notably psoriatic arthritis, psoriasis, atopic dermatitis, asthma, and chronic obstructive pulmonary disease (COPD). Examples of such drugs inclu...

Claims

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Application Information

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IPC IPC(8): A61K31/44A61K9/00A61K9/06A61K9/12A61K47/10A61K47/24
CPCA61K45/06A61K9/0014A61K47/10A61K47/24A61K31/44A61K9/122A61K9/06A61P11/06A61P11/08
Inventor WELGUS, HOWARDTHURSTON, JR., ARCHIE W.OSBORNE, DAVID W.
Owner ARCUTIS INC
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