Innovative Approaches in Levodopa Nasal Spray Formulation: A Review on Excipient Role and Selection

Levodopa is a precursor to dopamine, widely used for Parkinson’s disease. However, its oral administration is associated with erratic absorption and reduced bioavailability due to extensive first-pass metabolism. Nasal delivery circumvents these limitations by enabling direct drug transport to the brain via the olfactory route, leading to rapid onset of action and improved therapeutic efficacy.   Parkinson’s disease (PD) is a debilitating motor neuron disease that affects the dopaminergic neurons within the nigral-striatal and surrounding pathways. Pathologically, the cause of the disease is a dopamine (DA) deficiency in the basal ganglia of the brain. The clinical manifestations begin to appear when dopaminergic neuron loss is up to 70–80%. Levodopa (l-dopa), the metabolic precursor of DA, has been regarded as the standard for treating PD . L-Dopa works by replacing the DA that would be normally released by the substantia nigra DA pathway. It can cross the blood brain barrier (BBB) via a saturable transporter, i.e., a large neutral amino acid active carrier system. In the brain, it is converted to DA by l-aromatic amino acid decarboxylase (AAAD, also known as dopa decarboxylase), primarily within the presynaptic terminals of dopaminergic neurons in the striatum. However, l-dopa is converted to DA outside the CNS as well, so that relatively little unchanged drug reaches the cerebral circulation when l-dopa is administered alone. Moreover, the DA released into the circulation by peripheral conversion of l-dopa produces undesirable effects. Levodopa is typically administered orally in large doses, but there are several factors that are believed to be responsible for the inefficiency of the oral dosage forms. Firstly, L-dopa undergoes carrier-mediated active transport absorption in the intestine, and the major absorption site for L-dopa is the duodenum. Such site-specific absorption limits the extent of absorption of orally administered L-dopa. Secondly, L-dopa undergoes extensive metabolism in the gastrointestinal wall during the absorption process. L-dopa is metabolized to several products, the most important one being dopamine, which is responsible for the major peripheral side-effects. Finally, inter- and intra-individual variability in the degree of the first-pass effect is the main cause of the common difficulty of maintaining an effective therapeutic regimen with L-dopa.

Particularly aiming at central nervous system (CNS) diseases, including schizophrenia, migraines, Parkinson’s, etc., intranasal drug delivery via the olfactory and trigeminal routes directly to the brain is capable of providing much more effective drug concentration at lower doses and reduced risk for adverse reactions [ Because of this, a long felt need exists for an alternative and improved method for the utilization of L-dopa in Parkinson’s patients. Recently, the nasal route of administration has received a great deal of attention as a convenient and reliable method for the administration of drugs and serves as an alternative to intravenous administration (Chien 1992). Some of the advantages of this alternative route for the delivery of therapeutics Nasal delivery of L-dopa has the potential to solve such problems by enhanced local drug concentration in the brain. Nasal administration offers a non-invasive pathway to delivery drugs for treating both local and systemic diseases, with several advantages of bypassing the blood-brain barrier, avoiding hepatic first-pass elimination, and reducing side effects The formulation of a levodopa nasal spray requires careful selection of excipients to enhance drug solubility, permeability, stability, and patient adherence. This review discusses various excipients and their role in optimizing levodopa nasal formulations. 

History: -

5. Consideration of History and Past Activity Occurrences in the Development of Levodopa Nasal Spray.

The development of a nasal spray formulation for levodopa (L-dopa) is rooted in extensive research on its pharmacokinetics, bioavailability challenges, and prior attempts at alternative delivery routes.  Historical studies provide valuable insights into overcoming barriers associated with oral administration and optimizing nasal formulations for improved therapeutic outcomes in Parkinson’s disease. 

1. Limitations of Traditional Oral Levodopa Therapy

Oral levodopa has been the standard treatment for Parkinson’s disease for decades. However, significant challenges exist: 

- Peripheral metabolism & low bioavailability: A large portion of orally administered levodopa is metabolized in the gut and liver before reaching the brain, necessitating the use of decarboxylase inhibitors (e.g., carbidopa). 

- Delayed onset & fluctuating plasma levels: Oral levodopa exhibits slow absorption and erratic plasma concentrations, contributing to motor fluctuations, including “ON-OFF” phenomena and dyskinesia. 

- Gastrointestinal complications: Nausea, vomiting, and delayed gastric emptying further limit its effectiveness, especially in advanced Parkinson’s disease. 

2. Historical Attempts at Alternative Delivery Routes

Recognizing these limitations, researchers have explored various non-oral routes, including: 

- Intravenous levodopa: Provides rapid symptom relief but is impractical for long-term management. 

- Transdermal patches: Investigated for sustained delivery but limited by poor permeability of levodopa through the skin. 

- Inhalation therapy: Approved formulations like levodopa inhalation powder (Inbrija®) offer rapid onset but require coordination and patient compliance. 

3. Early Nasal Delivery Studies & Challenges

The nasal route emerged as a promising alternative due to its high vascularization, rapid drug absorption, and potential for bypassing first-pass metabolism. However, early studies faced several barriers: 

- Poor solubility & permeability: Levodopa’s hydrophilic nature limits passive diffusion across the nasal mucosa. 

- Short residence time: The mucociliary clearance mechanism rapidly removes drugs from the nasal cavity. 

- Irritation concerns: Repeated nasal administration of some excipients led to local irritation and inflammation. 

4. Evolution of Nasal Formulations

To address these challenges, researchers explored novel formulation strategies: 

• Use of absorption enhancers: Cyclodextrins (e.g., hydroxypropyl-β-cyclodextrin) improved solubility and permeability. 
• Mucoadhesive polymers: Chitosan, hyaluronate, hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP) prolonged nasal residence time. 
• Particle engineering technologies: 

• Spray drying produced optimized powder formulations. 

• Supercritical fluid techniques enhanced uniformity and bioavailability.
• Microfluidic approaches: More recent advancements involve the use of microfluidic spray drying (MFSD) to create uniform microparticles with tailored absorption properties. 

5. Clinical Implications & Recent Advances

- Studies on levodopa-carbidopa nasal sprays (e.g., CVT-301/Acorda Therapeutics) demonstrated rapid onset of action and improved “ON” time in Parkinson’s patients. 

- Advances in nanoparticle-based delivery and lipid-based carriers offer potential improvements in drug permeability and stability. 

- 3D-printed nasal casts are being used to model deposition patterns and optimize spray formulations.  The historical evolution of levodopa delivery highlights the need for precision-engineered nasal formulations to address the shortcomings of oral therapy. By leveraging knowledge from past attempts and integrating advanced formulation strategies, researchers are working toward a clinically viable nasal spray with improved bioavailability, rapid onset, and reduced motor fluctuations for Parkinson’s patients.

Advantages of Nasal Delivery for L levodopa:-

- Bypassing First-Pass Metabolism:  Improves systemic bioavailability. 

- Rapid Onset of Action: Direct absorption into systemic circulation and potential nose-to-brain transport. 

- Improved Patient Compliance: Non-invasive, painless alternative to oral and parenteral routes. 

- Enhanced Bioavailability: Avoids enzymatic degradation in the gastrointestinal tract. 

Key Challenges in Levodopa Nasal Formulations :-

- Poor aqueous solubility. 

- Chemical and enzymatic instability in nasal mucosa. 

- Limited permeability across nasal epithelium. 

- Risk of mucosal irritation with certain excipients. 

Role of Excipients in Levodopa Nasal Spray Formulations :-

Excipients play a crucial role in overcoming formulation challenges. They are classified based on their function: 

1. Solubilizers and Co-Solvents 

Levodopa has limited solubility in water; therefore, solubilizers are essential for formulation stability. 

- Cyclodextrins (e.g., Hydroxypropyl-β-cyclodextrin): Forms inclusion complexes to enhance solubility and stability. 

- Ethanol and Propylene Glycol: Used as co-solvents to improve drug dissolution. 

2. Permeation Enhancers

Nasal permeability is a major barrier to levodopa absorption. Permeation enhancers help in transiently modifying tight junctions. 

- Chitosan: A mucoadhesive polymer that enhances drug retention and absorption. 

- Sodium Lauryl Sulfate (SLS): Increases membrane fluidity but may cause irritation. 

- Lecithin and Fatty Acid Derivatives: Improve membrane permeability with minimal irritation. 

3. Mucoadhesive Polymers 

Enhancing nasal residence time improves drug absorption and prolongs therapeutic effects. 

- Carbopol 934P: Increases viscosity and bioadhesion, reducing drug clearance from the nasal cavity. 

- HPMC (Hydroxypropyl Methylcellulose): Acts as a viscosity enhancer and stabilizer. 

4. Buffering Agents and pH Modifier

Levodopa is pH-sensitive, requiring optimal pH adjustment for stability and absorption. 

• Citrate and Phosphate Buffers: Maintain an optimal pH (around 5.5–6.5) for nasal mucosal compatibility. 

5. Preservatives and Antioxidants

Prevent microbial growth and oxidation of levodopa. 

- Benzalkonium Chloride: Common antimicrobial preservative but may cause mucosal irritation. 

- Ascorbic Acid and Sodium Metabisulfite: Antioxidants to prevent levodopa degradation. 

5. Comparative Analysis of Excipient Performance 

A comparative study of different excipients used in levodopa nasal formulations is summarized in Table no.01

Table no. 01:-  Different Excipients with respect to their roles

Each component plays a crucial role in ensuring optimal therapeutic effects. Below is a detailed analysis of each excipient:-

1. Levodopa (Active Pharmaceutical Ingredient – API)

- Function : Levodopa is a dopamine precursor that helps manage Parkinson’s disease by replenishing dopamine levels in the brain.

- Need in Nasal Spray : Due to poor oral bioavailability and first-pass metabolism, nasal delivery provides a rapid onset of action and avoids gastrointestinal degradation.

2. Ascorbic Acid (Stabilizer / Antioxidant)

- Function: Prevents oxidation of Levodopa, which is highly prone to degradation when exposed to oxygen.

- Comparative Advantage: Ascorbic acid increases formulation stability and shelf life while maintaining Levodopa’s potency.

- Alternative: Other antioxidants like sodium metabisulfite or EDTA could be used, but ascorbic acid is safer and more biocompatible.

3. Thiourea / Chitosan (Permeation Enhancer)

- Function : Enhances nasal mucosal permeability, allowing better absorption of Levodopa into systemic circulation.

- Comparison:

- Thiourea enhances absorption by modifying mucosal tight junctions but has safety concerns.

- Chitosan, a natural biopolymer, enhances permeation while also acting as a bioadhesive, increasing nasal retention time.

- Preferred Option: Chitosan is more biocompatible and widely used for nasal drug delivery.

4. Chlorobutanol (Preservative)

- Function: Prevents microbial contamination in the formulation.

- Comparison:

- Commonly used in ophthalmic and nasal formulations.

- Safer compared to parabens but can cause mild irritation.

- Alternative: Benzalkonium chloride (BAK) is another option, but it may cause mucosal irritation with prolonged use.

- Preferred Choice: Chlorobutanol offers effective preservation without significant irritation.

5. Carbopol 934 (Mucoadhesive Agent)

- Function : Enhances nasal retention time, improving drug absorption by prolonging contact with the nasal mucosa.

- Comparison:

- Increases viscosity, preventing rapid drainage of the formulation.

- Alternative: Hydroxypropyl methylcellulose (HPMC) or sodium alginate can also be used, but Carbopol 934 is widely preferred due to its superior mucoadhesive properties.

- Preferred Choice: Carbopol 934 provides better bioadhesion, ensuring sustained drug absorption.

6. Phosphate Buffer (pH Adjuster)

- Function: Maintains the pH of the formulation within an optimal range for stability and mucosal compatibility.

- Comparison:

- Helps maintain Levodopa in a soluble and stable form.

- Nasal pH range (4.5–6.5) is crucial to avoid irritation.

- Alternative: Citrate buffer can be used, but phosphate buffer is preferred for better physiological compatibility.

- Preferred Choice : Phosphate buffer is ideal for maintaining Levodopa stability in a nasal formulation.

7. Distilled Water (Vehicle)

- Function: Serves as the main solvent for dissolving and dispersing all excipients and the API.

- Comparison:

- Free from impurities and endotoxins, ensuring safety.

- Alternative: Sterile saline can be used but may affect drug solubility.

- Preferred Choice: Distilled water is used to ensure a pure and stable formulation.

6. Innovations in Levodopa Nasal Formulations

Recent advancements in nasal spray technology focus on improving drug targeting and patient adherence. 

- Nanoparticle-Based Systems: Enhances bioavailability and controlled drug release. 

- Liposomes and Niosomes: Protect levodopa from enzymatic degradation and improve permeability. 

- In Situ Gelling Systems: Increases nasal residence time, enhancing drug absorption. 

- Powder-Based Nasal Delivery: Alternative to liquid sprays, offering stability advantages. 

7. Future Perspectives and Challenges

Despite promising results, levodopa nasal sprays require further research to address: 

- Long-Term Stability Issues 

- Patient Variability in Nasal Absorption

- Regulatory Approval Challenges 

- Scalability of Novel Formulations for Commercialization

Mechanisms of Intranasal Transport :-

Intracellular Pathway: L-DOPA nanoparticles (NPs) are taken up by trigeminal and olfactory sensory neurons, transported via endocytosis through the Golgi Apparatus, and released in the olfactory bulb via exosomes.

Extracellular Pathway: L-DOPA diffuses through tight junctions (TJs) between neurons and moves along the paracellular space, ultimately reaching the CNS.

Overcoming Challenges of Oral Levodopa