Faculdade de Farmácia da Universidade de Lisboa

Unidade Curricular - Ciências de Dados no Fabrico de Medicamentos​

Ano Letivo 2024/2025

Development of a Dry Powder Inhaler

Formulation of Sumatriptan for Acute Migraine
Treatment

Docente: João Lopes

Discentes:

Rodrigo Santos nº 70542

Ghassen Chouat nº 73446

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 Index
1. Project Overview​ 3
1.1 Introduction and Objectives​ 3
1.2 Methodology​ 3
2. Competitive Landscape and Therapeutic Gap​ 4
2.1 Why Migraine is a Priority in Portugal​ 4
2.2 Why Triptans Are the Standard but Can Be Improved​ 5
2.3 Triptans Marketed in Portugal​ 6
2.4 Market Gap for Triptan DPI in Portugal​ 6
3. Formulation and Delivery System Proposal​ 8
3.1 Triptans action mechanism​ 8
3.2 API and Dose Justification​ 8
3.3 Formulation Strategy​ 9
3.4 Inhaler Device​ 9
3.5 Innovation Summary​ 10
4. Safety and Efficacy Assessment​ 12
4.1 Sumatriptan: Clinical Efficacy and Safety Profile​ 12
4.2 Dry Powder Inhalers: Theoretical Safety and Efficacy Considerations​ 12
4.3 Safety and Efficacy Summary​ 12
5. Market Forecast and Impact Assessment​ 14
5.1 Target Population​ 14
5.2 Triptan Usage Profile​ 14
5.3 Revenue Projection​ 15
6. Final Considerations​ 16

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1. Project Overview

1.1 Introduction and Objectives

This project was developed as part of a strategic challenge to evaluate the feasibility of
launching a new pharmaceutical product in the Portuguese market, leveraging the
technological capabilities of Hovione.​
Given the high prevalence, functional impact, and therapeutic gaps associated with
migraine, we identified this indication as a promising entry point for innovation.​
The main objective is to propose a differentiated formulation of sumatriptan, a first-line
treatment for moderate-to-severe migraine, using a dry powder inhaler (DPI) platform
aligned with Hovione’s expertise.

1.2 Methodology

The work was structured around a combination of scientific, technical, and market-based
approaches. The methodology included:

●​ Literature review of clinical efficacy and safety data on sumatriptan and other triptans
●​ Comparative analysis of therapeutic areas and drug delivery systems
●​ Evaluation of inhalation technologies, excipients, and Hovione’s existing device
platforms
●​ Search of regulatory databases (EMA, FDA) for relevant pharmacokinetic and safety
data
●​ Market sizing estimates, based on Portuguese epidemiological and prescription data
●​ Use of tools like Power BI for exploratory data treatment and visualization

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2. Competitive Landscape and Therapeutic Gap
2.1 Why Migraine is a Priority in Portugal

●​ Affects ~1.5 to 2 million people (16–20% of adult population)

●​ One of the top 10 global causes of disability (WHO)
●​ Peak prevalence in working-age adults (20–50), especially women (3:1)
●​ Underdiagnosed and undertreated (40% without adequate care)

Comparison across therapeutic areas:

Therapeutic Area Prevalence Industry Remarks

(%) Attention

Cardiovascular 20–25% Very High Strong public and private

investment

Metabolic (e.g., ~13% High Established, focus on continuous

diabetes) innovation

Gastrointestinal 10–15% Moderate Generic-driven, less innovation

Neurological (e.g., ~20% Low – Underprioritized given

migraine) Medium functional impact

Mental Health ~25% Growing Recent pharma focus

Comparison with other neurological diseases:

Disease Prevalence (%) Remarks

Migraine 16–20% Most prevalent neurological

condition

Epilepsy ~0.6% Controlled with structured care

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Parkinson's ~0.2% Mainly elderly population

Early-onset Alzheimer ~1% Rising with population aging

Multiple sclerosis ~0.1% High visibility, low incidence

2.2 Why Triptans Are the Standard but Can Be Improved

●​ First-line for moderate to severe migraine

●​ High efficacy (~60–80%) if taken early
●​ Limitations of current formulations:
○​ Oral – slow onset, low GI tolerance
○​ Nasal – affected by congestion, taste issues
○​ SC – fast, but invasive and impractical

Comparison with other acute treatments:

Treatment Type Examples Efficacy Onset Limitations

Triptans Sumatriptan, High 15–45 Vascular risks, high

Rizatriptan (60–80%) min cost

Analgesics Paracetamol, Moderate 30–60 Poor results in

Ibuprofen min severe attacks

Potent NSAIDs Naproxen, Diclofenac Moderate– 30–60 GI issues

High min

Ergot derivatives Ergotamine, DHE Variable 30–60 Low tolerability

min

Antiemetic + Metoclopramide + Moderate 45–60 Only if nausea is

Analgesic Paracetamol min prominent

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 2.3 Triptans Marketed in Portugal

Triptan Brand Route Status in Notes

Portugal

Sumatriptan Imigran Oral, Nasal, Marketed Most versatile

SC

Rizatriptan Maxalt Oral, Marketed Fast-acting, palatable

Orodispers.

Zolmitriptan Zomig Oral, Marketed Moderate onset

Orodispers.

Eletriptan Relpax Oral Marketed CYP3A4 interactions

Frovatriptan Migpriv Oral Marketed Long half-life, less suited for

acute use

Almotriptan Almogran Oral Marketed Good tolerability

2.4 Market Gap for Triptan DPI in Portugal

Route Exists in Limitations DPI Opportunity

Portugal?

Oral Yes Slow, first-pass Faster onset

metabolism

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Orodispersible Yes GI dependence, mild Consistent dosing
effect

Subcutaneous Yes Invasive, complex use Non-invasive, better

compliance

Nasal Spray Yes Variable with Avoids nasal mucosa

congestion, taste altogether

Dry Powder No — High absorption, portable,

Inhaler innovative

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3. Formulation and Delivery System Proposal
3.1 Triptans action mechanism

Triptans act primarily as selective serotonin (5-HT₁B/₁D) receptor agonists, targeting both
peripheral and central mechanisms involved in migraine pathophysiology:

●​ 5-HT₁B receptors are located on cerebral and meningeal blood vessels. Their
activation causes vasoconstriction, reversing the pathological vasodilation that
contributes to migraine pain.
●​ 5-HT₁D receptors are found on perivascular trigeminal nerve endings and
centrally within the trigeminocervical complex. Their activation inhibits the
release of pro-inflammatory neuropeptides (such as CGRP and substance P),
blocking nociceptive signal transmission.

To reach both receptor populations, systemic absorption is essential. While the

vasculature is accessible peripherally, central targets require partial penetration of the
blood-brain barrier — a property sumatriptan achieves due to its low molecular weight and
moderate lipophilicity.

3.2 API and Dose Justification

The active pharmaceutical ingredient (API) selected for this formulation is sumatriptan
base, the most widely used and studied triptan, already commercialized in various
administration routes including oral, subcutaneous, and nasal.

Reference product (nasal spray):

●​ Imigran nasal spray (available in Portugal) contains 20 mg of sumatriptan per dose.

●​ However, the nasal bioavailability is only ~15–20%, due to first-pass nasal
metabolism and losses from mucociliary clearance ("drip loss").
●​ This translates into an effectively absorbed dose of ~3–4 mg per application.

Pulmonary route:

●​ Pulmonary dry powder delivery provides rapid systemic absorption through the
alveolar surface, bypassing first-pass metabolism. While no triptan is currently
approved for this route, inhaled delivery of similarly small, lipophilic molecules has
shown systemic bioavailability in the range of 40–60%.
●​ Given that ~4 mg of sumatriptan is systemically absorbed from a 20 mg nasal spray,
a pulmonary dose of 6–8 mg is expected to provide comparable plasma levels,
allowing the drug to reach both peripheral and central 5-HT₁B/₁D receptors.
●​ This dose remains within regulatory and clinical safety thresholds and aims to ensure
a fast onset of action via CNS penetration.

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3.3 Formulation Strategy

In dry powder inhalers, excipients are critical for powder flowability, aerodispersibility,
and lung deposition, but must also be non-toxic and well tolerated in the pulmonary
system.

Selected excipient: Mannitol

●​ Approved for inhalation use

●​ Non-lactose alternative suitable for lactose-intolerant patients
●​ Well tolerated, chemically stable and non-hygroscopic
●​ Provides consistent aerodynamic performance as a carrier

Optional excipients:

●​ L-leucine or magnesium stearate may be included in trace amounts (0.2–1% w/w)

to improve powder deagglomeration and reduce retention inside the capsule or
device walls.

Component Amount Function

Sumatriptan base 8 mg Active ingredient

Mannitol (inhalable ~25 mg Carrier for dispersion and

grade) deposition

L-leucine / Mg-stearate ~0.3 mg (optional) Improve powder flow/dispersion

Total ~33.3 mg Stable, single-dose inhalable

powder formulation

3.4 Inhaler Device

Feature TwinCaps® (Hovione)

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Type Single-use, passive dry powder inhaler

Dose Pre-filled hard capsule, inserted before use

preparation

Mechanism Breath-actuated, no external energy required

Portability Compact, disposable, hygienic

Patient Easy to operate, no cleaning or maintenance

usability

Pulmonary Delivers API directly to the lungs via deep inhalation

delivery

Hovione Developed and patented by Hovione

platform

Compatibility Ideal for unit-dose formulations targeting acute symptom

control

3.5 Innovation Summary

Element Added Value

First DPI triptan in No current competitors

Portugal

Suitable during Works regardless of nasal

attacks congestion

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Fast & stable delivery Avoids GI, taste, first-pass limitations

Hovione-ready Uses existing DPI tech platform

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4. Safety and Efficacy Assessment
4.1 Sumatriptan: Clinical Efficacy and Safety Profile

Sumatriptan is a selective 5-HT₁B/₁D receptor agonist widely used for the acute treatment of
migraine. Its efficacy and safety have been confirmed through multiple clinical studies:

●​ Efficacy:
○​ Subcutaneous administration of 6 mg provided pain relief in 89.5% of attacks
and complete pain resolution in 71% of cases.
○​ Oral doses of 50 mg achieved pain relief in 59–62% of cases within 4 hours,
significantly outperforming placebo (32–42%).
●​ Safety:
○​ The most common adverse events include atypical sensations (5–6%),
pressure or tightness (6–8%), and fatigue (2–3%).
○​ Serious cardiovascular events are rare but may include coronary vasospasm
or myocardial ischemia; sumatriptan is contraindicated in patients with a
history of cardiovascular disease.

4.2 Dry Powder Inhalers: Theoretical Safety and Efficacy Considerations

Dry powder inhalers are a well-established delivery method in respiratory and systemic
therapies. Although no triptan is currently available in this format, extensive evidence
supports the theoretical viability of such a product.

●​ Efficacy:
○​ Inhalation delivery can achieve systemic absorption comparable to
intravenous administration, with rapid onset of action, as demonstrated with
APIs such as fentanyl and levodopa.
○​ Estimated bioavailability for inhaled small-molecule drugs typically ranges
between 40–60%, depending on formulation, particle engineering, and inhaler
efficiency.
●​ Safety:
○​ Excipients commonly used in DPIs are approved for pulmonary use and have
been well tolerated in marketed products.
○​ Modern single-use DPI devices ensure accurate dosing and minimize user
error, improving patient safety and adherence.

4.3 Safety and Efficacy Summary

Aspect Sumatriptan Dry Powder Inhalers (DPIs)

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 Efficacy Pain relief in up to 89.5% of Comparable onset and systemic
attacks; complete relief in exposure observed in studies with other
71% (SC) rapidly acting APIs

Safety Common AEs: atypical Inhalation excipients (e.g., mannitol)

sensations, pressure, fatigue; approved; consistent delivery minimizes
rare CV events risk

Bioavailabilit 14% (oral), 96% (SC), 17% Estimated 40–60%, depending on

y (nasal) formulation and device

Despite the absence of direct clinical data for a pulmonary DPI formulation of
sumatriptan, the theoretical foundation is robust. The API has a well-established safety
and efficacy profile across various delivery routes, and dry powder inhalation is widely
recognized as a viable alternative for rapid systemic drug absorption.​
Considering the physicochemical properties of sumatriptan, the favorable safety record of
inhalable excipients such as mannitol, and the technical reliability of unit-dose DPI devices, it
is reasonable to assume that such a product could be developed with acceptable safety
and therapeutic performance.​
Further clinical trials would, of course, be necessary to confirm these projections.

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5. Market Forecast and Impact Assessment

5.1 Target Population

Migraine prevalence in Portugal affects approximately 16–20% of the adult population, which
corresponds to around 1.6 to 2 million individuals. Among them, it is estimated that about
25% experience moderate to severe episodes requiring triptan therapy, resulting in a target
population of approximately 500,000 patients.

Demographic Segmentation:

●​ Gender: 75% women (3:1 ratio)

●​ Age: Peak prevalence between 20 and 50 years old, with significant socioeconomic
impact.
●​ Current treatment status: Around 40% of patients are either undiagnosed or
inadequately treated.

Category Estimated Value

Adult population ~10 million

Prevalence 16–20%

Moderate/severe cases ~500,000

(25%) patients

Female patients (75%) ~375,000

Age 20–50 ~70%

5.2 Triptan Usage Profile

Based on observational studies and market reports, triptan usage patterns vary significantly
across patients. The average is estimated at 2 doses per week, but patient adherence can
be segmented into three main profiles:

Adherence % of Patients Annual Doses per

Profile Patient

Low (1/week) 30% 52

Moderate (2/week) 50% 104

High (3–4/week) 20% 156–208

Estimated weighted average: ~110 doses/year/patient

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With a target population of 500,000 patients, the potential market volume ranges
between 50 and 100 million doses annually, depending on adherence rates and
market penetration.

5.3 Revenue Projection

Revenue projections are based on an average market price of €10 per dose, with alternative
pricing scenarios considered. To simulate progressive market adoption over a 3-year period:

Base Scenario:

Year Adoption Rate Patients Annual Revenue

Doses (€10/dose)

Year 1 1% 5,000 550,000 €5.5 million

Year 2 5% 25,000 2.75 million €27.5 million

Year 3 10% 50,000 5.5 million €55 million

Note: Based on a weighted average of 110 doses/year.

Estimated Costs and Break-Even (Simplified)

Category Annual Estimate

Manufacturing costs (30%) €16.5 million

Marketing & distribution (20%) €11 million

Estimated gross margin (50%) €27.5 million

Break-even is expected to occur between Year 2 and Year 3, depending on initial

investments in clinical trials, regulatory approval, and marketing efforts.

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6. Final Considerations
Migraine represents a significant unmet need, affecting over 15% of the Portuguese
population and often insufficiently treated with current formulations.​
Sumatriptan remains the most widely used triptan, with proven efficacy and tolerability, yet its
current delivery forms present limitations in terms of speed, convenience, and tolerability.

The proposed dry powder inhaler (DPI) formulation is technically feasible, theoretically
safe, and therapeutically relevant. It leverages Hovione’s existing inhalation technologies
(TwinCaps®), avoids nasal mucosal variability, and offers a potentially faster onset without
the drawbacks of subcutaneous, nasal spray or oral administration.

Although further clinical development will be necessary, the scientific rationale, formulation
proposal, and market analysis together support this product as an innovative, viable, and
strategically aligned opportunity for Hovione.

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