DESIGN OF EXPERIMENT AVENUE FOR DEVELOPMENT AND …

www.wjpps.com Vol 9, Issue 6, 2020.

1742

Payal et al. World Journal of Pharmacy and Pharmaceutical Sciences


Palghadmal et al. World Journal of Pharmacy and Pharmaceutical Sciences

DESIGN OF EXPERIMENT AVENUE FOR DEVELOPMENT AND

VALIDATION OF RP-HPLC- PDA METHOD FOR DETERMINATION

OF APREMILAST IN BULK TABLET FORMULATION

Palghadmal P. J.*, Bhawar S. B., Kolhe M. H.

Department of Pharmaceutical Quality Assurance Technique, Pravara Rural College of

Pharmacy, Pravaranagar, Tal-Rahata, Dist-Ahamadnagar.

ABSTRACT

Apremilast, an orally administered small molecule inhibitor of

phosphodiesterase 4 (PDE4), has been licensed by the US Food and

Drug Administration for the management of active psoriatic

arthritis (March 21, 2014) and moderate to severe plaque psoriasis

(September 23, 2014). It has got approval from Drug Controller

General of India for marketing in India in 2017. The drug has

drawn much attention from the practising dermatologists for its

commendable safety profile and prescription convenience.

Introduced initially as an orally administered small molecule in

psoriasis patients, the drug has now been used in various other

indications as evident by the recent surge in literature for its off-

label uses. Being a relatively new drug in the treatment

armamentarium of psoriasis and other inflammatory dermatoses; in

this review, we will discuss various practical aspects of prescribing oral apremilast,

based on the current and emerging literature.

• Apremilast is an oral first-in-class phosphodiesterase 4 inhibitor that was approved by

the FDA for the treatment of adults with active psoriatic arthritis and adults with

moderate to severe plaque psoriasis.

• The recommended daily dose is 30 mg twice daily and initial doses should be titrated

over the course of about a week to reduce gastrointestinal adverse reactions.

• Apremilast was shown to be moderately effective in clinical trials at reducing

symptoms of psoriatic arthritis including tender and swollen joints and physical

functioning (ACR20) in patients who have failed previous treatments. Concomitant

Article Received on

19 April 2020,

Revised on 09 May 2020,

Accepted on 29 May 2020

DOI: 10.20959/wjpps20206-16404

*Corresponding Author

Palghadmal P. J.

Department of

Pharmaceutical Quality

Assurance Technique,

Pravara Rural College of

Pharmacy, Pravaranagar,

Tal-Rahata, Dist-

Ahamadnagar.

d

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 6, 1742-1754 Review Article ISSN 2278 – 4357


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treatment with methotrexate or other conventional systemic disease-modifying ant

rheumatic drugs (DMARDs) was allowed. Results from 4 clinical trials showed NNTs

ranging from 4 -10 with 30 mg twice daily dosing.

• Apremilast was shown to be moderately effective in clinical trials at improving

symptoms and quality of life for patients with plaque psoriasis. Results from two

clinical trials showed statistically significant improvements in 75% improvement in

Psoriasis Area and Severity Index (PASI-75) with 20 mg twice daily and 30 mg twice

daily dosing.

• Depression may develop or worsen during therapy; educate patients and use caution

in patients with a history of depression or suicidality. The most common adverse

reactions reported were diarrhoea, headache, nausea, and upper respiratory tract

infection.

KEYWORDS: Apremilast, phosphodiesterase, psoriatic arthritis, methotrexate.

INTRODUCTION

• Apremilast is phosphodiesterase-4 and an Immuno modulating agent used for

treatment of refractory Psoriatic arthritis.

• Apremilast (APL) is a new therapeutic medicinal agent

• accepted for the management of psoriasis and psoriasis

• arthritis (Baumer et al. 2007; Keating 2017).

• Apremilast, brand name Otezla among others, is a medication for the treatment of

certain types of psoriasis and psoriatic arthritis. It may also be useful for other

immune system related inflammatory diseases. Wikipedia

• Formula: C22H24N2O7S

• Molar mass: 460.5 g/mol

• ChemSpider ID: 9736448

• ChEMBL Id: 514800

• Trade name: Otezla, Aplex, others

• ChemSpider ID: 9736448

Chemical composition

• Apremilast is chemically identified as N- [2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-

(methylsulfonyl) ethyl]-2, 3-dihydro-1, 3-dioxo-1H-isoindol-4-yl] acetamide. The

molecular formula and weight of apremilast are C22H24N2O7S and 460.5 g/mole,


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respectively.

Uses

1. This medication is used to treat a certain type of arthritis (psoriatic arthritis).

2. Apremilast is also used to treat a certain type of skin condition (moderate to severe

plaque psoriasis).

3. Apremilast belongs to a class of drugs known as phosphodiesterase 4 (PDE4)

inhibitors.

4. For the treatment of psoriatic arthritis, it decreases pain and swelling, and may help

improve flexibility in the affected joints.

5. For the treatment of plaque psoriasis, it may help to reduce the redness, thickening,

and scaling of the skin that occurs with this condition.

6. Apremilast is also used to treat mouth sores in people who have Behcet's disease. It

helps to reduce the pain and improve the healing of these mouth sores.

Side effects

1. Diarrhoea, nausea/vomiting, loss of appetite, headache, or weight loss may occur. If any of

these effects persist or worsen, tell your doctor or pharmacist promptly.

2. Remember that your doctor has prescribed this medication because he or she has judged

that the benefit to you is greater than the risk of side effects. Many people using this

medication do not have serious side effects.

3. Tell your doctor right away if you have any serious side effects, including: severe

nausea/vomiting/ diarrhoea.

Apremilast

Small molecule inhibitor of phosphodiesterase(PDE)- 4 (main PDE in inflammatory


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cells)

Results in down regulation of immune mediators

Pharmacodynamics

Selective inhibitor of Phosphodiesterase – 4

Effects on immune mediators

Inhibited production of (in vitro & in animals)

Chemokines ( CXCL9 , CXCL10)

Interleukins (IL2 , 5 ,IL 12 A, IL 13)

Cytokines like interferon α & γ, TNF α and GM- CSF

Adaptive immune mechanism minimally affected - No significant effect on B cell

immunoglobulin production

Effects on immune mediators

Exploratory analysis of Phase 3 study

Palace 1: Psoriatic arthritis patients significantly (p < 0.05) reduced circulating levels

proinflammatory innate Th 1 immunity components relative to placebo over 4 – 24 weeks

of therapy.

Effects on skin and other parameters

Effects on skin and other parameters

QT not prolonged –when given in dosages of 50mg twice daily.


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Pharmacokinetic

Undergoes extensive metabolism

Pharmacokinetic


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Pharmacokinetic

Analyic method

Validation of HPLC Method

Linearity

The linearity of analytical method for APR was determined by studying standard

calibration curves. The range of analytical method was decided from the interval

between upper and lower level of calibration curves by plotting the log curve.

Accuracy

Accuracy of the method was assessed by standard addition method at three different

concentration levels i.e. 50%, 100, 150%. Standard concentration of 10, 20 and 30 μg/ml

was added into 20 μg/ml of tablet concentration. The % Recoveries was calculated by

applying regression equation.

Precision

The precision of an analytical method was studied by performing intermediate precision.


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Limit of deteetion and of quautitation

Detection limit and quantitation limit were determined based on the standard deviation of

y- intercepts of calibration curves and average slope of calibration curves.

LOD = 3.3 × Standard deviation of intercept

---------------------------------------------------

Slope

LOQ = 10× Standard deviation of intercept

-----------------------------------------------

Slope

Robustness

Standard solution of APR (30 μg/ml)) were used and analyzed at different flow rate (0.7,

0.8, 0.9 ml/min) and wavelength (228, 230, 232 nm).

Ruggedness

Ruggedness of the method was checked by two different analysts keeping same

experimental and environmental conditions. An appropriate concentration 30 μg/ml of

APR was subjected to analysis and concentration was determined. This procedure was

repeated three times.

UV-Visible Spectrophotometric Methods

Standard solution having concentration range of 2, 4, 6, 8, 10 μg/ml of APR was prepared.

Absorbances of these solutions were recorded at 230 nm. Calibration curve was plotted,

absorbance vs concentration.


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Data of calibration curve by UV

Chromatographic Methods

Selection of Analytical Wavelength

The standard solutions of APR (10 μg/ml) in mobile phase were scanned in the UV

region of 190 - 400 nm and the overlain spectra were recorded. It was observed that APR

drugs showed the absorbance at 230 nm.

Typical chromatograph of Apremilast by HPLC at Optimized condition


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Validation Parameter

This Method was Validate Apremilast was found in the Range from 98065 -101.69%.

Paper review

By study of some searches and findings following samples are represents the line study

related to the topic

1. By Harry- January 9, 2020

Otezla (apremilast) for Plaque Psoriasis: "The percentages here are pretty close to what

the clinical trials have shown. Only about 30-35% of people get to 75% clear. That's

roughly the same percentage of people who gave a 7 or higher review. But the severity of

some of the side effects are certainly concerning, as is the development of even worse

psoriasis when the drug is stopped (and sometimes before). At best, it is a tricky

cost/benefit call. Mainly comes down to whether someone is feeling lucky! Or not."

2. A Review of phosphodiesterase-inhibition and the potential role for phosphodiesterase

4- inhibitors in clinical dermatology Farah Moustafa1, Steven R Feldman 1, 2, 3

Dermatology Online Journal 20 (5): 1

Center for Dermatology Research, Departments of[1]

Dermatology,[2]

Pathology and[3]

Public Health Sciences; Wake Forest School of Medicine; Winston-Salem, North

Carolina.

Background

Phosphodiesterase inhibitors are commonly used drugs. Specific phosphodiesterase

inhibitors with anti-inflammatory properties are being assessed as dermatological

treatments.

Purpose

To describe important aspects of phosphodiesterase inhibition and the safety and efficacy

of 2 phosphodiesterase- 4 inhibitors being studied for the treatment of dermatologic

diseases.

Methods

We did a non-systematic analysis of literature on phosphodiesterase inhibition

followed by a review of published information on apremilast and topical AN2728

and their use for psoriasis and atopic dermatitis.


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Findings

Apremilast and topical AN2728 have modest efficacy in treatment of psoriasis.

Apremilast achieved PASI-75 scores ranging from 24-33%. In phase 2 studies, AN2728

had modest efficacy for psoriasis (40% of patients achieved a ≥ 2 grade improvement as

assessed by the Overall target Plaque Severity Score). In phase 2 studies of AN2728 use

in atopic dermatitis, subjects achieved a 71% improvement from baseline Atopic

Dermatitis Severity Index.

CONCLUSION

Phosphodiesterase inhibitors constitute a widely used class of drugs that may see

growing use for inflammatory dermatologic diseases.

KEYWORDS

Apremilast, AN2728, Psoriasis, Atopic Dermatitis, phosphodiesterase inhibitor,

inflammation

Clinical Uses

a. This medication is used to treat a certain type of arthritis (psoriatic arthritis).

Apremilast is also used to treat a certain type of skin condition (moderate to severe

plaque psoriasis). Apremilast belongs to a class of drugs known as phosphodiesterase

4 (PDE4) inhibitors. For the treatment of psoriatic arthritis, it decreases pain and

swelling, and may help improve flexibility in the affected joints.

b. For the treatment of plaque psoriasis, it may help to reduce the redness, thickening,

and scaling of the skin that occurs with this condition.

c. Apremilast is also used to treat mouth sores in people who have Behcet's disease. It

helps to reduce the pain and improve the healing of these mouth sores.

d. Licensed uses of apremilast include management of moderate to severe plaque

psoriasis and active PsA not responding adequately to disease modifying ant

rheumatic drugs (DMARDs).

e. The drug has been extensively studied for these two indications. However, recently, it

is tried for many other indications where there is a role for camp mediated anti-

inflammatory action.

Current status

Apremilast is reasonably efficacious in psoriasis and PsA with potential clinical use in


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other inflammatory conditions.

Good safety profile, ease of oral administration without a need for screening or

ongoing laboratory monitoring makes it a well sought drug among dermatologists.

However, a low drug survival beyond 6–8 months as reported in recent real world

studies and a critical observation on cost effectiveness by NICE experts necessitate a

considered thought on its long-term use as a maintenance therapy.

Availability of newer formulations as 10 and 20 mg widens the scope of its use in

dose titrations in various settings.

Apremilast is a molecule with limited experience among dermatologists and near

future will witness its more comprehensive application in psoriasis, PsA, and various

inflammatory dermatomes.

1. PDE4 inhibitors with better patient tolerability and more specific mechanism of action

in psoriasis and inflammatory dermatomes should be a focus of immediate research.

2. Its safety and efficacy in paediatric age group is also an important area for further

exploration.

3. There is moderate quality evidence consistently showing apremilast to be a safe and

effective medication in the treatment of adults with moderate to severe psoriatic

arthritis or plaque psoriasis. For psoriatic arthritis, the clinical trials showed

improvement in clinical symptoms such as tender or swollen joints

CONCLUSION

• The reversed-phase high-performance liquid-chromatography method for analysis of

Apremilast was developed and validated as per ICH guidelines.

• Methanol composition with water 7:3 ratio in the mobile phase, were used to

construct a mathematical model and study the effects of these independent factors on

responses and effectiveness.

• In the present investigation, the developed and validated, UV Spectrophotometric

method were found to be simple, economical and rapid method. HPLC was found to

more precise, accurate, rugged and robust for determination of Apremilast. The results

and the statistical parameters demonstrate that the proposed UV spectrophotometric

and HPLC method is simple, rapid, specific, accurate and precise.

REFERENCE

1. Otezla [package insert]. Summit, NJ: Celgene Corporation; September, 2014.


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2. Hansen RB, Kavanaugh. Novel treatments with small molecules in psoriatic arthritis.

3. Curr Rheumatol Rep, 2014; 16: 443.

4. Pathan E, Abraham S, Van Rossen E, Withrington R, Keat A, Charles P, et al.

5. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing

spondylitis. Ann Rheum Dis, 2013; 72: 1475-1480.

6. Thompson BJ, Furniss M, Zhao W, Chakraborty B, Mackay-Wiggan J. An oral

phosphodiesterase inhibitor (apremilast) for inflammatory rosacea in adults: a pilot

study. JAMA Dermatol, 2014; 150(9): 1013.

7. Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of oral

phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch

Dermatol, 2012; 148(8): 890-897.

8. Souza AD, Strober BE, Merola JF, Oliver S, Franks AG. Apremilast for Discoid

Lupus Erythematosus: Results of a Phase 2, Open-Label, Single-Arm, Pilot Study. J

Drugs Dermatol, 2012; 11(10): 1224-1226.

9. Paul J, Foss CE, Hirano SA, Cunningham TD, Pariser DM. An open-label pilot study

of apremilast for the treatment of moderate to severe lichen planus: a case series. J

Am Acad Dermatol, 2013; 68(2): 255-261.

10. Liu LY, King BA. Lack of efficacy of apremilast in 9 patients with severe alopecia

areata. J Am Acad Dermatol, 2017; 77: 773-4.


Efficacy and safety of apremilast, an oral phosphodiesterase inhibitor, in ankylosing


https://www.rxlist.com/otezla-drug.htm#description

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362739/

13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622317/

14. Pincus, T. The American College of Rheumatology (ACR) core data set and

derivative "patient only" indices to assess rheumatoid arthritis. Clin Exp Rheumatol.,

2005; 23(5.39): S109-113.

15. Nagasawa, Hayato, Hideto Kameda, Naoya Sekiguchi, Koichi Amano, and Tsutomu

Takeuchi. Differences between the health assessment questionnaire disability index

(HAQ-DI) and the modified HAQ (mHAQ) score before and after infliximab

treatment in patients with rheumatoid arthritis. Mod Rheumatol 2010; 20(4): 337-

342.

16. Hansen RB, Kavanaugh. Novel treatments with small molecules in psoriatic arthritis.

https://www.rxlist.com/otezla-drug.htm





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Curr Rheumatol Rep, 2014; 16: 443.


Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing


18. Thompson BJ, Furniss M, Zhao W, Chakraborty B, Mackay-Wiggan J. An oral

phosphodiesterase inhibitor (apremilast) for inflammatory rosacea in adults: a pilot

study. JAMA Dermatol, 2014; 150(9): 1013.

19. Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of oral

phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol

2012; 148(8): 890-897.

20. Souza AD, Strober BE, Merola JF, Oliver S, Franks AG. Apremilast for Discoid

Lupus Erythematosus: Results of a Phase 2, Open-Label, Single-Arm, Pilot Study. J

Drugs Dermatol, 2012; 11(10): 1224-1226.

21. Paul J, Foss CE, Hirano SA, Cunningham TD, Pariser DM. An open-label pilot study

of apremilast for the treatment of moderate to severe lichen planus: a case series. J

Am Acad Dermatol., 2013; 68(2): 255-261.

22. Liu LY, King BA. Lack of efficacy of apremilast in 9 patients with severe alopecia

areata. J Am Acad Dermatol, 2017; 77: 773-4.

23. Pincus, T. The American College of Rheumatology (ACR) core data set and

derivative "patient only" indices to assess rheumatoid arthritis. Clin Exp Rheumatol.,

2005; 23(5.39): S109-113.

24. Nagasawa, Hayato, Hideto Kameda, Naoya Sekiguchi, Koichi Amano, and Tsutomu

Takeuchi. Differences between the health assessment questionnaire disability index

(HAQ-DI) and the modified HAQ (mHAQ) score before and after infliximab

treatment in patients with rheumatoid arthritis. Mod Rheumatol, 2010; 20(4): 337-

342.

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