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表紙：筋痙縮の世界市場-2023年～2030年
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1345450

筋痙縮の世界市場-2023年～2030年

Global Muscle Spasticity Market - 2023-2030
出版日: | 発行: DataM Intelligence | ページ情報: 英文 186 Pages | 納期: 約2営業日

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筋痙縮の世界市場-2023年～2030年
出版日: 2023年09月06日
発行: DataM Intelligence
ページ情報: 英文 186 Pages
納期: 約2営業日
ご注意事項 :
本レポートは最新情報反映のため適宜更新し、内容構成変更を行う場合があります。ご検討の際はお問い合わせください。
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  • 概要
  • 目次
概要

概要

筋痙縮の世界市場は、2022年に42億米ドルに達し、2023～2030年の予測期間にCAGR 8.1%で成長し、2030年には77億米ドルに達すると予測されます。

多発性硬化症、脳性麻痺、脊髄損傷、脳卒中などの神経疾患に起因することが多い筋痙縮の治療市場には、投薬療法や医療機器、治療法が含まれます。

筋痙縮を頻繁に引き起こす加齢に関連した神経疾患は、高齢者に多く見られます。治療や管理技術に対するニーズは、高齢化とともに高まっています。筋痙縮に対する医療サービス、診断、治療へのアクセスの向上は、市場の拡大を促します。これは特に新興市場で顕著です。

しかし、推奨される治療法を患者が遵守することが困難な場合があり、これは治療成績や市場拡大に影響を及ぼします。患者集団によっては、安全性への懸念から特定の筋痙縮治療、特に投薬療法しか使用しない場合もあります。

ダイナミクス

研究活動の活発化

2022年5月、Saol Therapeutics社の第II相RAISE Spasticity Trialに最初の患者が登録されたと、株式非公開の臨床段階の製薬企業であるSaol Therapeutics社は本日発表しました。RAISE痙縮試験では、独自の化学神経溶解注射剤であるSL-1002の試験が行われています。SL-1002は現在Saol Therapeutics社が開発中です。四肢痙縮成人患者におけるSL-1002の安全性、薬物動態、有効性を評価するため、二重盲検プラセボ対照単回昇降用量漸増試験が実施されています（NCT05311215）。

プラセボに対するSL-1002の単回投与後の総合的な安全性プロファイルが主要評価項目です。Tardieuスケール、Clinical Global Impression of Change（CGI-C）、Modified Ashworth Score（MAS）のような指標は、副次的評価項目の例ですが、それだけではありません。SL-1002とその代謝産物の代謝とクリアランスに関連したヒトの薬物動態と薬力学の特徴付けは、さらなる副次的測定です。

治療の選択肢の増加

脊髄と脳の運動ニューロンに沿った脱髄は、筋痙縮患者の痙縮を引き起こします。痙縮によってもたらされる軽度の硬直は、立ったり寝返りを打ったりする際に患者をより強く支えるため、時として有利に働くことがあります。また、人によってはより適した薬もあります。主治医と相談して初めて、このような選択肢をとることができます。従来の治療法では改善しない重症例では、他の治療法を試すこともあります。

これには、より長期的な治療や、神経や筋肉を一時的に遮断する処置（ボトックスやマイオブロック注射など）が含まれます。例えば、手術によって特定の神経や腱を切断したり、化学的に筋肉を不活性化したりする方法があります。痙縮の治療には、以下の薬剤が使用できます：バリウム（ジアゼパム）、ガブロフェン（バクロフェン注射剤）、ザナフレックス錠剤・カプセル（塩酸チザニジン）、バクロフェン（以前はリオレザールとして販売されていた）。

筋痙縮患者の増加

2023年にStat Pearlsに掲載された論文によると、脳損傷、脳卒中、脳性麻痺、多発性硬化症、外傷、脊髄損傷は痙縮の数ある病因のほんの一部に過ぎません。脳卒中患者における痙縮の有病率を調査した研究では、脳卒中患者の42.6％が痙縮を経験し、15.6％が重度の痙縮を経験しています。脳性麻痺における痙縮の有病率を調査した別の研究では、90％の人に痙縮の亜型がみられました。

重度の痙縮は患者の生活に大きな影響を及ぼし、日常生活活動から精神衛生、さらには収入にまで影響を及ぼします。しかし、四肢、特に下肢が弱い患者にとっては、痙縮がある方が移乗や歩行が容易になるため、有利な場合もあります。このような理由から、痙縮を評価することは、医療専門家が治療法の有効性を評価する上で非常に重要なことです。

意識向上と教育

筋痙縮のような医学的疾患を持つ患者が、その疾患の性質、原因、症状、可能性のある治療法について理解できるよう、意識向上のための取り組みが行われています。知識が豊富な患者は、自分自身で治療を決定することができます。筋痙縮の症状や指標を理解することは、早期診断や早期介入に役立ち、治療効果や患者の生活の質を向上させる可能性があります。患者は、啓発キャンペーンのおかげで、薬剤、治療法、生活習慣の改善など、利用可能なすべての治療法について学んだ後、自分の必要性に応じて最善の治療方針を選択することができます。

高額な治療費

必要な医療や医薬品へのアクセスは、高額な治療費によって妨げられることがあります。その結果、医療が行き届かなかったり遅れたりして、健康被害を悪化させる可能性があります。自己負担金、免責金額、薬代など、多額の自己負担金が患者やその家族に発生する可能性があります。こうした経済的責任から、ストレスが増大し、経済的に不安定になる可能性があります。

低所得者や社会から疎外された人々は、高額な治療費の影響を不当に受け、医療の不平等を拡大する可能性があります。その結果、健康格差や医療への不平等なアクセスが生じる可能性があります。

副作用と忍容性

痙縮の治療に使用される筋弛緩薬の多くは、患者に眠気や疲労感を与え、日常的な作業や認知活動の能力を損なう可能性があります。一部の薬剤は筋力低下を引き起こし、痙縮の症状を悪化させることがあります。ある種の薬剤はめまいやふらつきを引き起こすことがあり、そのために人はバランスを保つことが難しくなり、日常的な家事を安全に行うことができなくなります。

筋痙縮の治療法の中には、吐き気や嘔吐などの消化器系の副作用があるものもあります。薬によっては認知機能を損なう可能性があり、記憶力や集中力に問題が生じます。まれに、薬に対するアレルギー反応を起こすことがありますが、その程度は、軽度の皮疹から生命を脅かすアナフィラキシーショックまで様々です。

目次

第1章 調査手法と調査範囲

第2章 定義と概要

第3章 エグゼクティブサマリー

第4章 市場力学

  • 影響要因
    • 促進要因
      • 研究活動の活発化
      • 治療の選択肢の増加
      • 筋痙縮患者の増加
      • 認知と教育
    • 抑制要因
      • 高額な治療費
      • 副作用と安全性への懸念
    • 機会
    • 影響分析

第5章 産業分析

  • ポーターのファイブフォース分析
  • サプライチェーン分析
  • 価格分析
  • 規制分析
  • ロシア・ウクライナ戦争の影響分析
  • DMIの見解

第6章 COVID-19分析

第7章 薬剤タイプ別

  • バクロフェン
  • ボツリヌス毒素
  • ジアゼパム
  • ダントロレンナトリウム
  • その他

第8章 投与経路別

  • 経口
  • 筋肉内
  • その他

第9章 流通チャネル別

  • 病院薬局
  • 小売薬局
  • オンライン薬局

第10章 地域別

  • 北米
    • 米国
    • カナダ
    • メキシコ
  • 欧州
    • ドイツ
    • 英国
    • フランス
    • イタリア
    • ロシア
    • その他欧州
  • 南米
    • ブラジル
    • アルゼンチン
    • その他南米
  • アジア太平洋
    • 中国
    • インド
    • 日本
    • オーストラリア
    • その他アジア太平洋
  • 中東・アフリカ

第11章 競合情勢

  • 競合シナリオ
  • 市況/シェア分析
  • M&A分析

第12章 企業プロファイル

  • Ipsen Pharma
    • 企業概要
    • 製品ポートフォリオと説明
    • 財務概要
    • 主な動向
  • Allergan
  • Acorda Therapeutics, Inc.
  • Merz Pharma
  • Novartis AG
  • Beximco Pharmaceuticals Ltd.
  • Zydus Cadila
  • Others

第13章 付録

目次
Product Code: PH6802

Overview

Global Muscle Spasticity Market reached US$ 4.2 billion in 2022 and is expected to reach US$ 7.7 billion by 2030, growing with a CAGR of 8.1% during the forecast period 2023-2030.

The market for treating muscle spasticity, which frequently results from neurological diseases such as multiple sclerosis, cerebral palsy, spinal cord injuries, and stroke, includes medications, medical devices, and therapies.

Age-related neurological disorders, which frequently result in muscle spasticity, are more common in older people. The need for treatments and management techniques grows along with the aging population. Greater access to medical services, diagnosis, and treatment for muscle spasticity encourages market expansion. This is especially true in emerging markets.

However, patient adherence to recommended treatments can be difficult, which has an impact on treatment results and market expansion. Certain patient populations may only use certain muscular spasticity treatments, especially medicines, due to safety concerns.

Dynamics

Increasing Research Activities

In May 2022, The first patient was enrolled in Saol Therapeutics' Phase 2 RAISE Spasticity Trial, the privately held, clinical-stage pharmaceutical business said today. In the RAISE Spasticity Trial, SL-1002, a unique, proprietary chemoneurolytic injectable, is being tested. It is currently being developed by Saol Therapeutics. To evaluate the safety, pharmacokinetics, and efficacy of SL-1002 in adult patients with limb spasticity, a double-blind, placebo-controlled, single ascending-dose escalation study is being conducted (NCT05311215).

The overall safety profile of SL-1002 following a single treatment exposure in contrast to placebo is the main outcome. Measures like the Tardieu scale, Clinical Global Impression of Change (CGI-C), and the Modified Ashworth Score (MAS) are examples of secondary endpoints, although they are not the only ones. Characterizing human pharmacokinetics and pharmacodynamics in relation to the metabolism and clearance of SL-1002 and its metabolites are additional secondary measurements.

The Increasing Treatment Options

Demyelination along the spinal cord and brain's motor neurons causes spasticity in MS patients. The minor stiffness brought on by spasticity can occasionally be advantageous since it gives people greater support when standing or turning. There are also drugs that may be more suitable for some people. Only after consulting with one's healthcare physician can these choices be taken. In severe cases that don't get better with conventional therapies, other therapies may be tried.

These include more long-term therapies as well as procedures that momentarily block the nerve and muscle (such as Botox or Myobloc injection). Examples include severing particular nerves or tendons through surgery and chemically deactivating a muscle. The following drugs can be used to treat spasticity: Valium (diazepam), Gablofen (baclofen injectable), Zanaflex tablets and capsules (tizanidine hydrochloride), and Baclofen (formerly marketed as Lioresal).

Increasing Patients with Muscle Spasticity

As per the article published in Stat Pearls in 2023, Brain injury, stroke, cerebral palsy, multiple sclerosis, trauma, and spinal cord injury are only a few of the many etiologies for spasticity. In a study that examined the prevalence of spasticity in stroke patients, 42.6% of stroke patients experienced spasticity, while 15.6% of patients experienced severe spasticity. 90% of the individuals in another study that examined the prevalence of spasticity in cerebral palsy had spastic subtypes.

Severe spasticity has a profound effect on a patient's life, affecting everything from daily living activities to mental health and even income. However, in individuals with weak limbs, particularly in the lower extremities, spasticity might be advantageous since it makes it easier for the patient to transfer or walk. For these reasons, assessing spasticity is crucial so that medical professionals may assess the efficacy of their treatment modalities.

Awareness and Education

Initiatives to raise awareness assist people with medical illnesses like muscle spasticity in understanding the nature of the condition, its causes, symptoms, and potential therapies. Patients who are more knowledgeable are better able to decide on their own care. Understanding the symptoms and indicators of muscular spasticity can help with an earlier diagnosis and intervention, which may enhance the effectiveness of the treatment and the patient's quality of life. Patients can choose the best course of action for their requirements after learning about all of the available treatment options, including drugs, treatments, and lifestyle modifications, thanks to awareness campaigns.

High Treatment Costs

Access to necessary medical care and pharmaceuticals may be hampered by high treatment expenses. This may result in poor or delayed medical care, which could exacerbate health consequences. Significant out-of-pocket costs, like as copayments, deductibles, and medication prices, could be incurred by patients and their families. Increased stress and financial instability may result from these financial responsibilities.

Low-income people and marginalized communities are disproportionately affected by high treatment costs, which can increase healthcare inequities. Health disparities and unequal access to care may result from this.

Side Effects and Tolerability

Many muscle relaxants used to treat spasticity can make a person feel sleepy or exhausted, which can impair their ability to carry out everyday tasks and operate cognitively. Some drugs may cause muscle weakness, which can make the symptoms of spasticity worse. Certain drugs can cause dizziness or lightheadedness, which makes it difficult for people to maintain balance and safely carry out daily chores.

Some treatments for muscle spasticity may have gastrointestinal side effects like nausea and vomiting. Some medicines have the potential to impair cognitive function, resulting in issues with memory and concentration. Rarely, people may develop allergic responses to drugs, which can range in severity from minor skin rashes to life-threatening anaphylactic shock.

Segment Analysis

The global muscle spasticity market is segmented based on drug type, route of administration, distribution channel and region.

Botulinum Toxin

As per the article published in Toxins in 2022, Cerebral palsy (CP), the most prevalent motor disability in childhood, is a disorder in which harm to the area of the brain that regulates body coordination eventually compromises the functionality of the musculoskeletal system. The majority of CP patients have spasticity, and one method for treating it is by focally injecting botulinum toxin type-A (BTX-A) into the afflicted muscles.

The goal of BTX-A is to reduce spasticity and enhance joint function by paralyzing the muscles, although it has been demonstrated to have some unanticipated side effects. Weakness and atrophy are the most overt symptoms of BTX-A injection on a muscle level. It's significant to note that extreme weakness, one of the most frequently reported negative effects, creates a separate risk factor for joint deterioration, which can then result in osteoarthritis.

Geographical Penetration

Advanced Healthcare Infrastructure

North America has been a dominant force in the global Muscle Spasticity market. Spasticity will affect between 25% and 43% of survivors in the first year following a stroke. More young stroke survivors experience it. Spasticity can make it very difficult to perform basic everyday functions including eating, dressing, and bathing. These restrictions may make it more difficult for caregivers and lower quality of life.

Due to the high frequency of diseases like multiple sclerosis and cerebral palsy, muscle spasticity is comparatively widespread in North America. The precise incidence varies by geography and demographics of the populace. The existence of underlying neurological disorders is the main cause of muscle spasticity in North America. For instance, MS has a significant role in the region's incidences of spasticity.

Muscle spasticity management can be greatly aided by the accessibility and affordability of rehabilitation treatments including physical therapy, occupational therapy, and speech therapy. Muscle spasticity's causes and treatments are still being studied. Numerous pharmaceutical and research organizations in North America are engaged in developing treatments and other interventions to enhance the lives of people with this condition.

COVID-19 Impact Analysis

The outbreak of the COVID-19 pandemic in late 2019 created unprecedented challenges for industries worldwide, including the global muscle spasticity market. Due to lockdowns, social segregation policies, and the redirection of healthcare resources to COVID-19 care, numerous research trials for novel medications or treatments for muscle spasticity postponed or discontinued. This postponed the availability of potentially groundbreaking treatments.

Telemedicine has become more widely used because of the pandemic, enabling medical professionals to remotely monitor and discuss with patients. Patients with muscle spasticity were affected by this change in healthcare delivery since they could now get care without making in-person office visits.

Russia-Ukraine War Impact Analysis

Access to necessary drugs and therapies for ailments like muscle spasticity may be very difficult in areas where there is conflict. Patients may encounter difficulties getting the required therapies, and healthcare facilities may struggle to maintain enough stocks of pharmaceuticals.

The healthcare system in a nation can be put under tremendous strain during wartime. The availability of specialized care for disorders like muscle spasticity may be hampered by delays caused by the redirection of resources that would otherwise be used to treat chronic conditions to emergency care.

By Drug Type

  • Baclofen
  • Botulinum Toxin
  • Diazepam
  • Dantrolene Sodium
  • Others

By Route of Administration

  • Oral
  • Intramuscular
  • Others

By Distribution Channel

  • Hospital Pharmacies
  • Retail Pharmacies
  • Online Pharmacies

By Region

  • North America
    • U.S.
    • Canada
    • Mexico
  • Europe
    • Germany
    • UK
    • France
    • Italy
    • Spain
    • Rest of Europe
  • South America
    • Brazil
    • Argentina
    • Rest of South America
  • Asia-Pacific
    • China
    • India
    • Japan
    • Australia
    • Rest of Asia-Pacific
  • Middle East and Africa

Competitive Landscape

The major global players in the market include: Ipsen Pharma, Allergan, Acorda Therapeutics, Inc., Merz Pharma, Novartis AG, Beximco Pharmaceuticals Ltd., Zydus Cadila and others.

Why Purchase the Report?

  • To visualize the global muscle spasticity market segmentation based on drug type, route of administration, distribution channel and region as well as understand key commercial assets and players.
  • Identify commercial opportunities by analyzing trends and co-development.
  • Excel data sheet with numerous data points of muscle spasticity market-level with all segments.
  • PDF report consists of a comprehensive analysis after exhaustive qualitative interviews and an in-depth study.
  • Product mapping available as excel consisting of key products of all the major players.

The global muscle spasticity market report would provide approximately 55 tables, 57 figures and 186 Pages.

Target Audience 2023

  • Manufacturers/ Buyers
  • Industry Investors/Investment Bankers
  • Research Professionals
  • Emerging Companies

Table of Contents

1. Methodology and Scope

  • 1.1. Research Methodology
  • 1.2. Research Objective and Scope of the Report

2. Definition and Overview

3. Executive Summary

  • 3.1. Snippet by Drug Type
  • 3.2. Snippet by Route of Administration
  • 3.3. Snippet by Distribution Channel
  • 3.4. Snippet by Region

4. Dynamics

  • 4.1. Impacting Factors
    • 4.1.1. Drivers
      • 4.1.1.1. Increasing Research Activities
      • 4.1.1.2. The Increasing Treatment Options
      • 4.1.1.3. Increasing Patients with Muscle Spasticity
      • 4.1.1.4. Awareness and Education
    • 4.1.2. Restraints
      • 4.1.2.1.1. High Treatment Costs
      • 4.1.2.1.2. Side Effects and Safety Concerns
    • 4.1.3. Opportunity
    • 4.1.4. Impact Analysis

5. Industry Analysis

  • 5.1. Porter's Five Force Analysis
  • 5.2. Supply Chain Analysis
  • 5.3. Pricing Analysis
  • 5.4. Regulatory Analysis
  • 5.5. Russia-Ukraine War Impact Analysis
  • 5.6. DMI Opinion

6. COVID-19 Analysis

  • 6.1. Analysis of COVID-19
    • 6.1.1. Scenario Before COVID
    • 6.1.2. Scenario During COVID
    • 6.1.3. Scenario Post COVID
  • 6.2. Pricing Dynamics Amid COVID-19
  • 6.3. Demand-Supply Spectrum
  • 6.4. Government Initiatives Related to the Market During Pandemic
  • 6.5. Manufacturers Strategic Initiatives
  • 6.6. Conclusion

7. By Drug Type

  • 7.1. Introduction
    • 7.1.1. Market Size Analysis and Y-o-Y Growth Analysis (%), By Drug Type
    • 7.1.2. Market Attractiveness Index, By Drug Type
  • 7.2. Baclofen*
    • 7.2.1. Introduction
    • 7.2.2. Market Size Analysis and Y-o-Y Growth Analysis (%)
  • 7.3. Botulinum Toxin
  • 7.4. Diazepam
  • 7.5. Dantrolene Sodium
  • 7.6. Others

8. By Route of Administration

  • 8.1. Introduction
    • 8.1.1. Market Size Analysis and Y-o-Y Growth Analysis (%), By Route of Administration
    • 8.1.2. Market Attractiveness Index, By Route of Administration
  • 8.2. Oral*
    • 8.2.1. Introduction
    • 8.2.2. Market Size Analysis and Y-o-Y Growth Analysis (%)
  • 8.3. Intramuscular
  • 8.4. Others

9. By Distribution Channel

  • 9.1. Introduction
  • 9.2. Market Size Analysis and Y-o-Y Growth Analysis (%), By Distribution Channel
  • 9.3. Market Attractiveness Index, By Distribution Channel
  • 9.4. Hospital Pharmacies*
    • 9.4.1. Introduction
    • 9.4.2. Market Size Analysis and Y-o-Y Growth Analysis (%)
  • 9.5. Retail Pharmacies
  • 9.6. Online Pharmacies

10. By Region

  • 10.1. Introduction
    • 10.1.1. Market Size Analysis and Y-o-Y Growth Analysis (%), By Region
    • 10.1.2. Market Attractiveness Index, By Region
  • 10.2. North America
    • 10.2.1. Introduction
    • 10.2.2. Key Region-Specific Dynamics
    • 10.2.3. Market Size Analysis and Y-o-Y Growth Analysis (%), By Drug Type
    • 10.2.4. Market Size Analysis and Y-o-Y Growth Analysis (%), By Route of Administration
    • 10.2.5. Market Size Analysis and Y-o-Y Growth Analysis (%), By Distribution Channel
    • 10.2.6. Market Size Analysis and Y-o-Y Growth Analysis (%), By Country
      • 10.2.6.1. U.S.
      • 10.2.6.2. Canada
      • 10.2.6.3. Mexico
  • 10.3. Europe
    • 10.3.1. Introduction
    • 10.3.2. Key Region-Specific Dynamics
    • 10.3.3. Market Size Analysis and Y-o-Y Growth Analysis (%), By Drug Type
    • 10.3.4. Market Size Analysis and Y-o-Y Growth Analysis (%), By Route of Administration
    • 10.3.5. Market Size Analysis and Y-o-Y Growth Analysis (%), By Distribution Channel
    • 10.3.6. Market Size Analysis and Y-o-Y Growth Analysis (%), By Country
      • 10.3.6.1. Germany
      • 10.3.6.2. UK
      • 10.3.6.3. France
      • 10.3.6.4. Italy
      • 10.3.6.5. Russia
      • 10.3.6.6. Rest of Europe
  • 10.4. South America
    • 10.4.1. Introduction
    • 10.4.2. Key Region-Specific Dynamics
    • 10.4.3. Market Size Analysis and Y-o-Y Growth Analysis (%), By Drug Type
    • 10.4.4. Market Size Analysis and Y-o-Y Growth Analysis (%), By Route of Administration
    • 10.4.5. Market Size Analysis and Y-o-Y Growth Analysis (%), By Distribution Channel
    • 10.4.6. Market Size Analysis and Y-o-Y Growth Analysis (%), By Country
      • 10.4.6.1. Brazil
      • 10.4.6.2. Argentina
      • 10.4.6.3. Rest of South America
  • 10.5. Asia-Pacific
    • 10.5.1. Introduction
    • 10.5.2. Key Region-Specific Dynamics
    • 10.5.3. Market Size Analysis and Y-o-Y Growth Analysis (%), By Drug Type
    • 10.5.4. Market Size Analysis and Y-o-Y Growth Analysis (%), By Route of Administration
    • 10.5.5. Market Size Analysis and Y-o-Y Growth Analysis (%), By Distribution Channel
    • 10.5.6. Market Size Analysis and Y-o-Y Growth Analysis (%), By Country
      • 10.5.6.1. China
      • 10.5.6.2. India
      • 10.5.6.3. Japan
      • 10.5.6.4. Australia
      • 10.5.6.5. Rest of Asia-Pacific
  • 10.6. Middle East and Africa
    • 10.6.1. Introduction
    • 10.6.2. Key Region-Specific Dynamics
    • 10.6.3. Market Size Analysis and Y-o-Y Growth Analysis (%), By Drug Type
    • 10.6.4. Market Size Analysis and Y-o-Y Growth Analysis (%), By Route of Administration
    • 10.6.5. Market Size Analysis and Y-o-Y Growth Analysis (%), By Distribution Channel

11. Competitive Landscape

  • 11.1. Competitive Scenario
  • 11.2. Market Positioning/Share Analysis
  • 11.3. Mergers and Acquisitions Analysis

12. Company Profiles

  • 12.1. Ipsen Pharma*
    • 12.1.1. Company Overview
    • 12.1.2. Product Portfolio and Description
    • 12.1.3. Financial Overview
    • 12.1.4. Key Developments
  • 12.2. Allergan
  • 12.3. Acorda Therapeutics, Inc.
  • 12.4. Merz Pharma
  • 12.5. Novartis AG
  • 12.6. Beximco Pharmaceuticals Ltd.
  • 12.7. Zydus Cadila
  • 12.8. Others

LIST NOT EXHAUSTIVE

13. Appendix

  • 13.1. About Us and Services
  • 13.2. Contact Us