PharmDev360

Tuesday, April 30, 2024

Libervant™ - Diazepam buccal film for the treatment of acute seizures

On April 29, 2024 Aquestive Therapeutics, Inc. (NASDAQ: AQST) announced the FDA has approved Libervant™ (diazepam) Buccal Film for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy between 2 to 5 years of age. According to the news release, the film is placed onto the buccal mucosa inside the cheek where it adheres firmly and dissolves quickly, delivering a consistent dose of diazepam. (1)

On March 28 2023, Aquestive Therapeutics, Inc. announced it expanded its exclusive license and supply agreement with Atnahs Pharma UK Limited (“Pharmanovia”), a global pharmaceutical company that revitalizes, extends and expands the lifecycle of established medicines, for Libervant™ (diazepam) Buccal Film to cover the rest of the world, excluding the United States, Canada, and China. The original licensing agreement with Pharmanovia announced in September 2022 covered the European Union, United Kingdom, Sweden, Switzerland, and Norway, as well as countries in the Middle East and North Africa (MENA).

Libervant™ has several favorable characteristics and overcomes many of the disadvantages of other nonparenteral dosage forms used for acute seizure treatments. The thin film, which is less than the size of a postage stamp, is affixed to the buccal mucosa inside the cheek. Placement can be either by the patient or by a caregiver. Diazepam is absorbed transbucally and is also swallowed, so that a portion of the dose is transported to the stomach and absorbed by the small intestine. The polymer hydroxypropyl methylcellulose is used to hold diazepam and excipients in a uniform distribution throughout the film. Because of the uniform distribution, the dose can easily be adjusted by cutting the film. The film has a mucoadhesive surface so that it adheres to the buccal mucosa. It begins to dissolve immediately on application to the mucosa releasing diazepam. In studies with fasted healthy male volunteers, DBF doses of 5 mg to 15 mg exhibited rapid absorption and linear dose-proportional pharmacokinetics.

REFERENCES

(1) Aquestive Therapeutics Receives U.S. FDA Approval and Market Access for Libervant™ (diazepam) Buccal Film in Pediatric Patients Ages 2 to 5 and Provides Update on Anaphylm™ (epinephrine) Sublingual Film, Globe Newswire, Aquestive Therapeutics, Inc., Mon, Apr 29, 2024, 4:00 AM PDT.

(2) Aquestive Therapeutics Expands License and Supply Agreement with Pharmanovia for Libervant™ (diazepam) Buccal Film to Additional Global Markets Globe Newswire, Aquestive Therapeutics, Inc., Wed, Mar 29, 2023

(3) Michael A. Rogawski et al, Diazepam buccal film for the treatment of acute seizures, Epilepsy and Behavior, 101(2019) 106537.

Wednesday, February 07, 2024

Outline of CMC for vaccines

Here's a breakdown of CMC specifically for vaccines:

Chemistry:

Drug substance - the antigen component itself, which can be:
- Inactivated or attenuated viruses or bacteria
- Purified proteins or carbohydrates derived from pathogens.
- Recombinant proteins expressed in cell cultures.
- Nucleic acids (DNA or RNA) encoding antigens.
- Conjugates of antigens with carrier molecules.
Drug product - the final, injectable form of the vaccine, containing the drug substance formulated with:
- Adjuvants: Enhance immune response.
- Preservatives: Maintain sterility.
- Stabilizers: Prevent degradation.
- Excipients: Fillers, buffers, etc.
Analytical methods - specific methods are established to characterize and quantify the antigen, impurities, and excipients.
Raw materials and excipients - selection and qualification to ensure purity, consistency, and suitability for vaccine production.

Manufacturing:

Process development: Designing a scalable and reproducible process for antigen production, purification, formulation, and filling.
Process validation: Demonstrating the consistency and control of the manufacturing process through extensive testing.
Quality control: Implementing measures throughout the process to ensure product quality and adherence to specifications.

Controls:

Stability studies: Evaluating the vaccine's shelf life under various storage conditions.
Packaging and storage: Defining appropriate packaging and storage protocols to maintain potency and sterility.
Batch release testing: Each batch undergoes rigorous testing to ensure it meets all quality standards before release.

Additional considerations for vaccine CMC:

Highly sensitive materials: Many vaccine components require careful handling and processing to avoid degradation or contamination.
Aseptic processing: Ensuring sterility throughout the manufacturing process is crucial for vaccine safety.
Regulatory requirements: Stringent regulations govern vaccine development, manufacturing, and testing, demanding detailed documentation and compliance.

For details, please review FDA guidance listed in the section of resources.

Resources:

FDA Guidance: Content & Format CMC for Vaccine & Related Product. Accessed on Feb 07, 2024.
Maria Monica Castellanos, CMC Strategies and Advanced Technologies for Vaccine Development to Boost Acceleration and Pandemic Preparedness, Vaccines (Basel). 2023 Jul; 11(7): 1153

Outline of CMC for Biologics

CMC (Chemistry, Manufacturing, and Controls) is a critical aspect of bringing biologics, such as vaccines, blood products, and gene therapies, to market. It ensures that the biologics are safe, pure, potent, and consistent between batches.

Here are the key steps involved in CMC for biologics:

Chemistry:
- Characterization of the biologic drug substance and drug product, including its structure, purity, and stability.
- Development of analytical methods to measure these attributes.
- Selection and qualification of raw materials and excipients.
Manufacturing:
- Development of a robust and scalable manufacturing process that consistently produces a high-quality product.
- Validation of the manufacturing process to ensure it meets all regulatory requirements.
- Implementation of quality control measures throughout the manufacturing process.
Controls:
- Development of stability studies to determine the shelf life of the biologic.
- Development of packaging and storage specifications to protect the biologic from degradation.
- Ongoing monitoring of the manufacturing process and product quality.

CMC documentation:

All of the CMC activities are documented in a comprehensive set of reports that are submitted to regulatory agencies, such as the FDA, for approval. This documentation is essential for ensuring the safety and efficacy of the biologic.

CMC considerations for biologics:

Biologics are complex molecules that can be difficult to characterize and manufacture.
The manufacturing process for biologics can be very sensitive to changes, so it is important to have a robust and well-controlled process.
Biologics can be very potent, so it is important to ensure that they are sterile and free of impurities.

In vitro vs. In vivo Performance of Gastric Retentive Dosage Forms: Bridging the Gap

Gastric retentive dosage forms (GRDFs) have seen significant progress in recent years, driven by their potential to improve drug delivery and patient compliance. Some key recent developments include multi-mechanistic approaches, and magnetic systems. In multi-mechanistic approaches, a combination of different mechanisms like floating, swelling, and bio-adhesion is used to achieve more robust and consistent gastric retention, even in the fasted state. And, in magnetic systems, magnetic nanoparticles are used within the dosage form allows for external control of its movement and positioning within the stomach. This allows a more precise drug delivery.

In the last few years, advanced materials and complicated manufacturing technology have also been applied in the GRDFs. New polymers with tailored properties are being developed to offer improved biocompatibility, controlled release profiles, and enhanced gastric retention capabilities. 3D printing technology allows for the creation of complex and customized GRDFs with precise drug distribution and release characteristics.

In clinical translation, more products are reached the market and patient compliance is improved. Several GRDFs have been approved by regulatory agencies in recent years, demonstrating the potential of this technology for clinical use. In improved patient compliance, GRDFs can reduce dosing frequency, which can improve patient adherence to treatment regimens.

Challenge: In vitro vs. in vivo performance

Accurately predicting the in vivo performance of GRDFs based on in vitro experiments remains a significant challenge. While in vitro tests offer valuable insights into the formulation's basic properties, the complex and dynamic environment of the human stomach introduces several factors not easily replicated in the lab. Here's a deeper look at the discrepancies and ongoing efforts to bridge the gap:

Key Discrepancies:

Dynamic vs. Static Conditions: In vitro tests typically use static media with fixed pH and agitation, while the stomach exhibits a dynamic environment with changing pH, viscosity, and gastric emptying rate. This can significantly impact the performance of GRDFs, like floating systems, whose buoyancy depends on gastric fluids.
Fed vs. Fasted State: Most in vitro tests are conducted in simulated fasted state conditions, but food intake significantly alters gastric motility and fluid composition, affecting GRDF behavior. Developing biorelevant fed-state dissolution methods is crucial for improved prediction.
Interindividual Variability: Stomach anatomy, physiology, and emptying rate vary considerably between individuals, impacting GRDF performance. In vitro models often lack this variability, potentially leading to misleading results.

Bridging the Gap:

Advanced In vitro Models: Researchers are developing more sophisticated in vitro models incorporating aspects of gastric physiology, like peristaltic movements and fed-state conditions. These models provide a more realistic environment for evaluating GRDFs.
Multi-method Approach: Utilizing a combination of in vitro tests with different dissolution media, agitation conditions, and biorelevant fed-state models can offer a more comprehensive understanding of GRDF behavior.
In silico Modeling: Computational simulations based on physiological data can predict the in vivo behavior of GRDFs, complementing in vitro experiments and informing formulation design.

Despite the challenges, researchers are continuously advancing in vitro models and methodologies to bridge the gap with in vivo performance. Combining these efforts within silico modeling holds great promise for optimizing GRDF design and ultimately achieving more predictable and effective drug delivery in the complex environment of the human stomach.

References:

Felix Schneider, et al, In Vitro and In Vivo Test Methods for the Evaluation of Gastroretentive Dosage Forms, Pharmaceutics. 2019 Aug; 11(8): 416.

Liza Józsa et al, Recent Options and Techniques to Assess Improved Bioavailability: In Vitro and Ex Vivo Methods, Pharmaceutics. 2023 Apr; 15(4): 1146.

Dhaivat C Parikh et al, In vitro and in vivo techniques to assess the performance of gastro-retentive drug delivery systems: a review, Expert Opin Drug Deliv . 2008 Sep;5(9):951-65.

Tuesday, February 06, 2024

EYLEA- aflibercept injection, solution, related lawsuits

EYLEA is a brand name for a medication called aflibercept. It is primarily used as an injection to treat various eye conditions.

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.

Indication:

Wet age-related macular degeneration (AMD): This is the most common use of EYLEA. It helps slow vision loss caused by abnormal blood vessel growth and leakage in the eye.
Diabetic macular edema (DME): This is swelling of the macula due to diabetes, and EYLEA can help improve vision and reduce swelling.
Retinal vein occlusion (RVO): Blockage of blood vessels in the retina can cause vision loss, and EYLEA can help restore vision and reduce swelling.
Diabetic retinopathy (DR): EYLEA may be used in some cases of advanced DR to reduce abnormal blood vessel growth and prevent vision loss.
Retinopathy of prematurity (ROP): In premature babies, EYLEA can help abnormal blood vessels in the eye develop normally, reducing the risk of vision problems.

Dosage form and Composition:

EYLEA is available as a sterile solution for injection into the eye (intravitreal injection).
EYLEA is a sterile, clear, and colorless to pale yellow solution. EYLEA does not contain anti-microbial preservative and is supplied as a sterile, aqueous solution for intravitreal injection in a single-dose pre-filled glass syringe or a single-dose glass vial designed to deliver 0.05 mL (50 microliters) of solution containing 2 mg of aflibercept in polysorbate 20 (0.015 mg), sodium chloride (0.117 mg), sodium phosphate monobasic monohydrate (0.055 mg), sodium phosphate dibasic heptahydrate (0.027 mg), sucrose (2.5 mg) and water for injection with a pH of 6.2.
EYLEA is a clear, colorless to pale yellow solution available as:
- Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose pre-filled glass syringe
- Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose glass vial.

Dose:

The dose and dosing schedule vary depending on the specific condition being treated and the individual patient's needs.
Typically, for wet AMD and DME, the initial dose is 2mg every 4 weeks for the first 5 injections, followed by 2mg every 8 weeks. Adjustments may be made based on individual response.

Route of administration:

EYLEA is administered as an intravitreal injection, directly into the vitreous humor (jelly-like substance) in the eye. This is done by an ophthalmologist in a clinical setting.

Effectiveness compared to its peer group:

EYLEA is considered one of the most effective medications for wet AMD and DME, comparable to other anti-VEGF drugs like Lucentis and Avastin.
Studies have shown similar effectiveness in terms of improving vision and reducing swelling.
The choice of medication may depend on factors such as individual response, cost, and potential side effects.

Adverse events:

Like any medication, EYLEA can have side effects. Some common side effects include:
- Eye pain, redness, or irritation
- Increased floaters
- Bleeding in the eye
- Eye infection (endophthalmitis)
- Increased blood pressure
- Nosebleeds
More serious side effects are rare but can occur, such as stroke, heart attack, or allergic reaction.

It is important to discuss the potential risks and benefits of EYLEA with your doctor before starting treatment.

Herb - Drug Interaction

Herbal medicines are often administered in combination with drugs for potential benefits of combining herbal medicines and drugs, even while acknowledging the interaction risks.

Pharmacokinetic and Pharmacodynamic Mechanisms

Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took dan shen herb. [1] Interactions between herbal medicines and drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms can also contribute to these interactions, dependent on the nature of the drug substance.

Duration of the Use of the Herbs

Dan Shen herb extract is widely used for the treatment and prevention of coronary heart disease and some other diseases. Dan Shen herb extract and theophylline are prescribed together to treat patients with asthma in some areas. In human, theophylline with low therapeutic index is mainly metabolized by CYP1A2. In vitro findings have shown that human CYP1A2 is inhibited by the ethyl acetate extract of Dan Shen Herb or Dan Shen pharmaceutical product. Thus, this suggests the possibility of drug interactions between Dan Shen extract and theophylline (CYP1A2 substrate). However, it was found that long-term oral intake of Dan Shen Herb extract does not change the basic pharmacokinetic parameters of theophylline in healthy subjects. Dose adjustment of theophylline thus may not be necessary in patients receiving concomitant therapy with Dan Shen extract. [2]

Components

Dan Shan Herb contains protocatechualdehyde, salvianolic acid B, tanshinone II(A), cryptotanshinone, etc. Some Dan Shen components in the hydrophilic extract depress the absorption of the protocatechualdehyde in rats, on the contrary, enhance the absorption of the salvianolic acid B and depress its elimination rate. The concomitant components in the lipophilic extract might enhance the absorption of cryptotanshinone and its distribution from the centre compartment to the peripheral compartment, and the metabolism to tanshinone II(A). [3]

Thus, the other components present in the extract of Chinese material medica had significant effect on the pharmacokinetics of its 'active components'. These components can exhibit competitive, synergistic, or metabolic effects. Therefore, the traditional Chinese medicine was a complicated system, It should be taken a scientific and holistic view in the research and development processes. [3]

Strong protein (albumin) binding of Dan Shen (50-70%) in serum was found. Salicylate, a chemical, is also strongly bound to albumin; it is also a widely used over-the-counter medicine in the U.S., we studied Danshen-salicylate interaction in vitro. No significant change in free Dan shen concentrations was observed when salicylate concentrations were subtherapeutic (< or = 100 microg/mL).

However, at therapeutic concentrations of salicylate (≥ = 150 microg/mL), free Dan Shen concentrations significantly decreased. On the other hand, Dan Shen potentially displaced salicylate from protein binding, thereby increasing the free salicylate concentration.

Always remember:

Consult a qualified healthcare professional before combining herbal medicines with conventional drugs.

REFERENCE

[1] Hu Z, et al, Herb-drug interactions: a literature review. Drugs. 2005;65(9):1239-82.

[2] Qiu F, Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers.Br J Clin Pharmacol. 2008 Feb;65(2):270-4.

[3] Song M, et al, Pharmacokinetic interactions between the main components in the extracts of Salvia miltiorrhiza Bge. in rat Yao Xue Xue Bao. 2007 Mar;42(3):301-7.

[4] Gupta D, et al, Drug-herb interactions: unexpected suppression of free Danshen concentrations by salicylate. J Clin Lab Anal. 2002;16(6):290-4.

Monday, February 05, 2024

Overview: Chronic fatigue syndrome or Myalgic encephalomyelitis

Chronic fatigue can be a confusing term, as it can refer to both a symptom and a specific medical condition. Here's a breakdown:

Symptom: Chronic fatigue is a feeling of excessive tiredness that lasts for at least 6 months and doesn't improve with rest. This can be a symptom of various underlying medical conditions, such as:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): This is a complex, long-term illness characterized by severe fatigue, post-exertional malaise (worsening symptoms after physical or mental activity), and other cognitive and physical symptoms.
Thyroid disorders: Hypothyroidism (underactive thyroid) can cause fatigue, along with other symptoms like weight gain and difficulty concentrating.
Anemia: This condition occurs when your blood doesn't have enough red blood cells, leading to fatigue, shortness of breath, and pale skin.
Sleep disorders: Sleep apnea, insomnia, and restless leg syndrome can disrupt sleep and lead to daytime fatigue.
Mental health conditions: Depression and anxiety can also cause fatigue and decreased energy levels.

Medical Condition: In specific cases, chronic fatigue itself can be diagnosed as a medical condition called Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This condition is characterized by specific criteria, including severe fatigue, post-exertional malaise, and cognitive difficulties, that are not explained by any other underlying medical condition.

Prevalence in the United States

Estimating the exact number of Americans with chronic fatigue is challenging because it can be a symptom of various conditions. However, some studies suggest that ME/CFS affects approximately 1-2.5 million Americans.

Symptoms of Chronic Fatigue Syndrome

Common symptoms of ME/CFS include:

feeling extremely tired all the time – you may find it very hard to do daily activities
still feeling tired after resting or sleeping
taking a long time to recover after physical activity
problems sleeping, such as waking up often during the night
problems with thinking, memory and concentration

Other symptoms include:

muscle or joint pain
headaches
a sore throat
flu-like symptoms.
feeling dizzy or sick
fast or irregular heartbeats

Causes of Chronic Fatigue

The exact causes of chronic fatigue are not fully understood, and it likely results from a complex interplay of factors. Some potential contributors include:

Viral infections: Some theories suggest that viruses like Epstein-Barr virus (EBV) might trigger ME/CFS in susceptible individuals.
Immune system dysfunction: Abnormalities in the immune system might play a role in ME/CFS.
Genetic factors: Certain genes might make some people more susceptible to developing ME/CFS.
Psychological factors: Stress, anxiety, and depression can worsen chronic fatigue symptoms.

Preventing Chronic Fatigue

Unfortunately, there is no guaranteed way to prevent chronic fatigue. However, focusing on healthy lifestyle habits can help reduce your risk of developing some underlying conditions that contribute to fatigue, such as:

Getting enough sleep: Aim for 7-8 hours of quality sleep per night.
Eating a healthy diet: Consume a balanced diet rich in fruits, vegetables, whole grains, and lean protein.
Exercising regularly: Engage in moderate-intensity exercise most days of the week.
Managing stress: Practice relaxation techniques like yoga or meditation.
Maintaining healthy relationships: Strong social connections can boost your emotional well-being.
Seeking regular medical checkups: Address any underlying medical conditions that might contribute to fatigue.

Treating ME/CFS

Treatment for ME/CFS aims to relieve the symptoms, i.e. conditions. Treatments include:

cognitive behavioral therapy
energy management
medicine to control symptoms such as pain and sleeping problems.

Some people with ME/CFS will improve over time, especially with treatment.

Many people with ME/CFS will need to adapt their daily routine and pattern of activities on a long-term basis. There may be periods when your symptoms get better or worse.

Important Note:

If you are experiencing chronic fatigue, it's important to consult a doctor to rule out any underlying medical conditions and discuss appropriate management strategies. They can help you determine the cause of your fatigue and recommend the best course of treatment.

Reference

1. Overview: Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), NHS website, accessed on February 05, 2024.

2. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Mayo Clinic website, accessed on February 05, 2024.

3. Joseph R. Yancey, Chronic fatigue syndrome: diagnosis and treatment, Am Fam Physician. 2012 Oct 15;86(8):741-6.

4. Myalgic encephalomyelitis/chronic fatigue syndrome, CDC, accessed on February 05, 2024

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Researchers' Note:

Recent Findings

A study investigated the clinical characteristics of young people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) following infectious mononucleosis (IM) caused by Epstein-Barr virus (EBV). They recruited 25 young people (12 adolescents and 13 young adults) who fulfilled the Canadian consensus criteria for ME/CFS following EBV-IM. The researchers assessed the frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) at the time of diagnosis and 6 and 12 months later.

They found that young adults had more severe symptoms and poorer physical functioning and HRQoL than adolescents throughout the study. After one year, more than half of the adolescents no longer met the diagnostic criteria for ME/CFS, while none of the young adults did. Adolescents who recovered showed improvement in physical functioning, symptom frequency and severity, and HRQoL, while young adults showed little improvement.

The researchers also found that EBV serology and EBV DNA load were not associated with distinct clinical features of ME/CFS, and there was no evidence of inflammation. The median time from symptom onset to ME/CFS diagnosis was 13.8 months.

These findings suggest that ME/CFS following EBV-IM is a more severe and persistent illness in young adults than in adolescents. There is a need for better biomarkers and more effective treatments for ME/CFS, especially in adults.

Reference:

Rafael Pricoco et al, Front Pediatr. 2024 Jan 18:11:1266738

Older Stories

Researchers have identified a family of retroviruses in patients with chronic fatigue syndrome, opening up a potentially promising new avenue of treatment for a debilitating disease that afflicts as many as four million Americans and 17 million people world-wide. [1]

Based on other recent research linking the syndrome to a retrovirus called XMRV, some doctors are already prescribing drugs approved for HIV for fatigue patients. Unfortunately,the syndrome has no effective treatments yet. The group of viruses identified in fatigue patients, called murine leukemia virus-related viruses, or MLV, are known to cause cancer and neurological problems in mice, but whether they cause disease in humans isn't known. XMRV is among several different members of the MLV family. [1]

XMRV is a identified human retrovirus that is similar to a group of mouse retroviruses (called murine leukemia viruses, or MLVs) scientists have known about for years. XMRV refers to xenotropic murine leukemia virus-related virus. It was first identified in 2006 in tissue samples from men with prostate cancer. [2]

As early as October 2009, scientists reported a potential association of XMRV with chronic fatigue syndrome (CFS). In this study, XMRV was detected in approximately two-thirds of patients diagnosed with CFS. They also identified DNA of XMRV in the blood cells of some healthy persons and suggested a potential for XMRV transmission by transfusion or transplantation. [2]

SOURCE [1] New Hope in Fatigue Fight wsj.com 2010 [2] CDC.gov

Sunday, February 04, 2024

REVIEW: JOENJA® (leniolisib) tablets**

JOENJA® (leniolisib) tablets, for oral use Initial U.S. Approval: 2023

Application Number: N217759
Approval Date: Mar 24, 2023
Applicant Holder Full Name: PHARMING TECHNOLOGIES BV

MECHANISM

Leniolisib inhibits PI3K-delta by blocking the active binding site of PI3K-delta. In cell-free isolated enzyme assays, leniolisib was selective for PI3K-delta over PI3K-alpha (28-fold), PI3K-beta (43-fold), and PI3K-gamma (257-fold), as well as the broader kinome. In cell-based assays, leniolisib reduced pAKT pathway activity and inhibited proliferation and activation of B and T cell subsets. Gain-of-function variants in the gene encoding the p110-delta catalytic subunit or loss of function variants in the gene encoding the p85-alpha regulatory subunit each cause hyperactivity of PI3K-delta. Leniolisib inhibits the signalling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/AKT pathway, and to the dysregulation of B and T cells.

INDICATION

JOENJA is a kinase inhibitor indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older.

DOSAGE ADMINSTRATION

Recommended dosage: 70 mg administered orally twice daily approximately 12 hours apart, with or without food, in adult and pediatric patients 12 years of age and older and weighing ≥45kg.

DOSAGE FORM AND STRENGTH

Tablets: 70 mg leniolisib

API

Leniolisib phosphate is a white to yellowish to yellowish-greenish powder. The aqueous solubility of leniolisib phosphate is pH dependent with decreasing solubility observed with increasing pH.

COMPOSITION/EXCIPIENTS

JOENJA film-coated tablets are for oral administration. Each tablet contains 70 mg of leniolisib (equivalent to 85 mg leniolisib phosphate) with the following inactive ingredients: colloidal silicon dioxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablet film-coating contains hydroxypropyl methylcellulose, iron oxide red, iron oxide yellow, polyethylene glycol, talc, and titanium dioxide.

The systemic drug exposure (AUC and Cmax) of leniolisib increased dose proportionally within the studied range of doses (20 to 140 mg twice a day dosing and single doses of 10 to 400 mg). During twice daily dosing approximately 12 hours apart, leniolisib accumulates approximately 1.4-fold (range of 1.0 to 2.2) in achieving steady-state, consistent with an effective half-life (t1/2) of approximately 7 hours. Steady state drug concentrations can be expected to be reached after approximately 2 to 3 days of JOENJA treatment.

In a placebo controlled, single and multiple ascending dose study in healthy participants, leniolisib median time to maximum plasma concentration (Tmax) occurred at about 1 hour postdose. Tmax appeared independent of dose and was not altered after multiple oral doses. Food is unlikely to have a clinically meaningful effect on the systemic exposure of leniolisib during JOENJA treatment.

The mean recovery of total 14C-radioactivity following a single oral dose of 70 mg 14C-leniolisib was 92.5% (67.0% and 25.5% recovered via feces and urine, respectively) 168 hours postdose. Unchanged leniolisib (6.32%) was the predominant drug-related material recovered in urine.

Leniolisib was 60% metabolized by the liver, with CYP3A4 being the most predominant enzyme involved (94.5%) in the primary oxidative metabolism of leniolisib with minor contribution from other enzymes (3.5% CYP3A5, 0.7% CYP1A2 and 0.4% CYP2D6). Intestinal secretion by BCRP as well as extrahepatic CYP1A1 cannot be excluded as excretion routes.

ADVERSE REACTIONS

Most common adverse reactions (incidence >10%) were headache, sinusitis, and atopic dermatitis.

Orange Book

8653092 - a chemical patent

Overview: Excipients used in mRNA vaccines - Moderna, Pfizer/BioNTech

Excipients play a crucial role in mRNA vaccines:

Protect the fragile mRNA sequence from degradation.

Facilitate delivery of the mRNA into cells and release it from internal compartments.

Modulate immune response: Different lipids can trigger specific types of immune reactions.

Examples of excipients in COVID-19 mRNA vaccines:

Moderna: messenger ribonucleic acid (mRNA), lipids (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]), tromethamine, tromethamine hydrochloride, acetic acid, sodium acetate, and sucrose

Pfizer/BioNTech: messenger ribonucleic acid (mRNA), lipids (((4-hydroxybutyl) azanediyl) bis(hexane-6,1-diyl), bis(2-hexyldecanoate), 2 [(polyethylene glycol)-2000] N, N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol), potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucrose.

Functions of Excipients

(Pfizer/BioNTech)

Lipids: Nanolipids, or tiny fat molecules, protect the mRNA and provide a “greasy” exterior that helps the mRNA slide inside cells.

Nanolipid components in the Pfzer-BioNTech vaccine include: ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol

Salts: Helping to balance the acidity in your body, the following salts are included in the Pfzer-BioNTech vaccine: potassium chloride, monobasic potassium phosphate, sodium chloride, and dibasic sodium phosphate dihydrate

Sugar: Basic table sugar, also known as sucrose, can also be found in the Pfzer-BioNTech vaccine. This ingredient helps the molecules maintain their shape during freezing.

(Moderna)

- Lipids: Nanolipids help deliver the mRNA to the vaccine recipient’s cells. Nanolipid components of the Moderna vaccine include: (SM-102, 1,2-dimyristoyl-rac-glycero3-methoxypolyethylene glycol-2000 [PEG2000-DMG], cholesterol, and 1,2-distearoyl-snglycero-3-phosphocholine [DSPC])

- The remaining excipients, including acids (acetic acid), acid stabilizers (tromethamine and tromethamine hydrochloride), salt (sodium acetate), and sugar (sucrose) all work together to maintain the stability of the vaccine after it’s produced.

In 2023, Lizhou Zhang and colleagues reported that the ionizable lipid, SM-102, in Moderna’s vaccine performed better than ALC-0315 in Pfizer-BioNTech’s vaccine for intramuscular delivery of mRNA and antibody production in mice and long-term stability at 4 °C. Moreover, Pfizer-BioNTech’s 5′ UTR and Moderna’s 3′ UTR outperform their counterparts in their contribution to transgene expression in mice. They further found that varying N1-methylpseudouridine content at the wobble position of mRNA has little effect on vaccine efficacy. (1)

Benefits of using excipients in mRNA vaccines:

Faster development and production: Easier to adapt existing platforms for new vaccines.

Reduced risk of pre-existing immunity: Compared to viral vector-based vaccines.

More targeted immune response: Can be tailored to specific needs.

Challenges with excipients:

Long-term safety data is limited.

Finding the right combination for different applications.

Overall, excipients are essential components of mRNA vaccines, offering numerous advantages but also requiring further research.

Reference:

Shireesh P. Apte, Excipients and mRNA Vaccines, J. Excipients and Food Chem. 11 (4) 2020.

What Ingredients are in the Covid-19 Vaccine? Connecticut Department of Public Health

(1) Lizhou Zhang et al, Effect of mRNA-LNP components of two globally-marketed COVID-19 vaccines on efficacy and stability, NPJ Vaccines. 2023; 8: 156.

Saturday, February 03, 2024

Overview: Excipients used in antibody products

There are many different excipients used in antibody products, but some of the most common ones include:

Buffers: These help to maintain the correct pH of the antibody product, which is important for its stability and activity. Common buffers used in antibody products include sodium phosphate, histidine, citrate, and acetate.

Sodium phosphate buffer Surfactants: These help to reduce surface tension and prevent the antibody from sticking to the container or other surfaces. Common surfactants used in antibody products include polysorbates (such as polysorbate 80 and polysorbate 20) and poloxamers.

Polysorbate 80 Tonicity agents: These help to adjust the osmotic pressure of the antibody product so that it is similar to the osmotic pressure of the body's fluids. This helps to prevent the product from causing irritation or pain when it is injected. Common tonicity agents used in antibody products include sodium chloride and mannitol.

Sodium chloride Sugars: These can act as bulking agents in lyophilized (freeze-dried) antibody products, and they can also help to stabilize the antibody. Common sugars used in antibody products include sucrose and trehalose.

Trehalose Amino acids: These can help to stabilize the antibody and prevent it from aggregating. Common amino acids used in antibody products include glycine and arginine.

Antioxidants: These help to protect the antibody from damage caused by free radicals. Common antioxidants used in antibody products include methionine and histidine.

The specific excipients used in a particular antibody product will depend on a number of factors, such as the properties of the antibody, the route of administration, the type of dosage forms (liquid, lyophilized powder) and the desired shelf life.

Here is a list of a few antibody-products for reference:

Avastin (bevacizumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brown solution in a single-dose vial for intravenous use. Avastin contains bevacizumab at a concentration of 25 mg/mL in either a 100 mg/4 mL or 400 mg/16 mL single-dose vial.

Each mL of solution contains 25 mg bevacizumab, α,α-trehalose dihydrate (60 mg), polysorbate 20 (0.4 mg), sodium phosphate dibasic, anhydrous (1.2 mg), sodium phosphate monobasic, monohydrate (5.8 mg), and Water for Injection, USP. The pH is 6.2.

Epogen (epoetin alfa) injection for intravenous or subcutaneous administration is formulated as a sterile, clear, colorless liquid in vials in multiple formulations. Single-dose vials, formulated with an isotonic sodium chloride/sodium citrate-buffered solution, are supplied in multiple strengths. Each single-dose 1 mL vial contains 2,000, 3,000, 4,000, or 10,000 Units of epoetin alfa, Albumin (Human) (2.5 mg), citric acid (0.06 mg), sodium chloride (5.9 mg), and sodium citrate (5.8 mg) in Water for Injection, USP (pH 6.9 ± 0.3). Multiple-dose, 2 mL vials contain 10,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), citric acid (0.11 mg), and sodium citrate (1.3 mg) per 1 mL Water for Injection, USP (pH 6.1 ± 0.3). Multiple-dose 1 mL vials contain 20,000 Units epoetin alfa, albumin (human) (2.5 mg), benzyl alcohol (1%), sodium chloride (8.2 mg), citric acid (0.11 mg), and sodium citrate (1.3 mg), per 1 mL in Water for Injection, USP (pH 6.1 ± 0.3).

Herceptin (trastuzumab) for injection is a sterile, white to pale yellow, preservative-free lyophilized powder with a cake-like appearance, for intravenous administration.

Each single-dose vial of Herceptin delivers 150 mg trastuzumab, 136.2 mg α,α-trehalose dihydrate, 3.4 mg L-histidine HCl monohydrate, 2.2 mg L-histidine, and 0.6 mg polysorbate 20. Reconstitution with 7.4 mL of sterile water for injection (SWFI) yields a solution containing 21 mg/mL trastuzumab that delivers 7.15 mL (150 mg trastuzumab), at a pH of approximately 6.

HERCEPTIN HYLECTA (trastuzumab and hyaluronidase) injection is a sterile, preservative-free, colorless to yellowish, clear to opalescent solution supplied in single-dose vials for subcutaneous administration.

HERCEPTIN HYLECTA is supplied as 600 mg trastuzumab and 10,000 units hyaluronidase per 5 mL in single-dose vials. Each mL of solution contains trastuzumab (120 mg), hyaluronidase (2,000 units), L-histidine (0.39 mg), L-histidine hydrochloride monohydrate (3.67 mg), L-methionine (1.49 mg), polysorbate 20 (0.4 mg), α,α-trehalose dihydrate (79.45 mg), and Water for Injection.

HUMIRA (adalimumab) injection is supplied as a sterile, preservative-free solution for subcutaneous administration. The drug product is supplied as either a single-dose, prefilled pen (HUMIRA Pen), as a single-dose, 1 mL prefilled glass syringe, or as a single-dose institutional use vial. Enclosed within the pen is a single-dose, 1 mL prefilled glass syringe. The solution of HUMIRA is clear and colorless, with a pH of about 5.2.

Each 80 mg/0.8 mL prefilled syringe or prefilled pen delivers 0.8 mL (80 mg) of drug product. Each 0.8 mL of HUMIRA contains adalimumab (80 mg), mannitol (33.6 mg), polysorbate 80 (0.8 mg), and Water for Injection, USP.

Each 40 mg/0.4 mL prefilled syringe or prefilled pen delivers 0.4 mL (40 mg) of drug product. Each 0.4 mL of HUMIRA contains adalimumab (40 mg), mannitol (16.8 mg), polysorbate 80 (0.4 mg), and Water for Injection, USP.

Each 40 mg/0.8 mL prefilled syringe, prefilled pen, or single-dose institutional use vial delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of HUMIRA contains adalimumab (40 mg), citric acid monohydrate (1.04 mg), dibasic sodium phosphate dihydrate (1.22 mg), mannitol (9.6 mg), monobasic sodium phosphate dihydrate (0.69 mg), polysorbate 80 (0.8 mg), sodium chloride (4.93 mg), sodium citrate (0.24 mg) and Water for Injection, USP. Sodium hydroxide is added as necessary to adjust pH.

Each 20 mg/0.2 mL prefilled syringe delivers 0.2 mL (20 mg) of drug product. Each 0.2 mL of HUMIRA contains adalimumab (20 mg), mannitol (8.4 mg), polysorbate 80 (0.2 mg), and Water for Injection, USP.

Each 20 mg/0.4 mL prefilled syringe delivers 0.4 mL (20 mg) of drug product. Each 0.4 mL of HUMIRA contains adalimumab (20 mg), citric acid monohydrate (0.52 mg), dibasic sodium phosphate dihydrate (0.61 mg), mannitol (4.8 mg), monobasic sodium phosphate dihydrate (0.34 mg), polysorbate 80 (0.4 mg), sodium chloride (2.47 mg), sodium citrate (0.12 mg) and Water for Injection, USP. Sodium hydroxide is added as necessary to adjust pH.

Each 10 mg/0.1 mL prefilled syringe delivers 0.1 mL (10 mg) of drug product. Each 0.1 mL of HUMIRA contains adalimumab (10 mg), mannitol (4.2 mg), polysorbate 80 (0.1 mg), and Water for Injection, USP.

Each 10 mg/0.2 mL prefilled syringe delivers 0.2 mL (10 mg) of drug product. Each 0.2 mL of HUMIRA contains adalimumab (10 mg), citric acid monohydrate (0.26 mg), dibasic sodium phosphate dihydrate (0.31 mg), mannitol (2.4 mg), monobasic sodium phosphate dihydrate (0.17 mg), polysorbate 80 (0.2 mg), sodium chloride (1.23 mg), sodium citrate (0.06 mg) and Water for Injection, USP. Sodium hydroxide is added as necessary to adjust pH.

Neulasta (Pegfilgrastim) is provided in two presentations:

Neulasta for manual subcutaneous injection is supplied in 0.6 mL prefilled syringes. The prefilled syringe does not bear graduation marks and is designed to deliver the entire contents of the syringe (6 mg/0.6 mL).
On-body injector (OBI) for Neulasta is supplied with a prefilled syringe containing 0.64 mL of Neulasta in solution that delivers 0.6 mL of Neulasta in solution when used with the OBI for Neulasta. The syringe does not bear graduation marks and is only to be used with the OBI for Neulasta.

The delivered 0.6 mL dose from either the prefilled syringe for manual subcutaneous injection or the OBI for Neulasta contains 6 mg pegfilgrastim (based on protein weight) in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 (0.02 mg), sodium (0.02 mg), and sorbitol (30 mg) in Water for Injection, USP.

NEUPOGEN (filgrastim) injection is a sterile‚ clear‚ colorless‚ preservative-free liquid containing filgrastim at a specific activity of 1.0 ± 0.6 × 108 U/mg (as measured by a cell mitogenesis assay). The product is available in single-dose vials for subcutaneous or intravenous use and prefilled syringes for subcutaneous use. The single-dose vials contain either 300 mcg/mL or 480 mcg/1.6 mL of filgrastim. The single-dose prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim. The NEUPOGEN drug product has a pH of 4.0. See table below for product composition of each single-dose vial or prefilled syringe.

	300 mcg/mL Vial	480 mcg/1.6 mL Vial	300 mcg/0.5 mL Syringe	480 mcg/0.8 mL Syringe
* quantity sufficient to make.
filgrastim	300 mcg	480 mcg	300 mcg	480 mcg
acetate	0.59 mg	0.94 mg	0.295 mg	0.472 mg
polysorbate 80	0.04 mg	0.064 mg	0.02 mg	0.032 mg
sodium	0.035 mg	0.056 mg	0.0175 mg	0.028 mg
sorbitol	50 mg	80 mg	25 mg	40 mg
water for Injection
USP q.s. ad*	1 mL	1.6 mL	0.5 mL	0.8 mL

REMICADE® (infliximab) for injection is supplied as a sterile, preservative-free, white, lyophilized powder for intravenous infusion after reconstitution and dilution. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the final concentration is 10 mg/mL and the resulting pH is approximately 7.2. Each single-dose vial contains 100 mg infliximab, dibasic sodium phosphate, dihydrate (6.1 mg), monobasic sodium phosphate, monohydrate (2.2 mg), polysorbate 80 (0.5 mg), and sucrose (500 mg).

RITUXAN (rituximab) injection is a sterile, preservative-free, clear, colorless solution for intravenous infusion. RITUXAN is supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-dose vials. Each mL of solution contains 10 mg rituximab, polysorbate 80 (0.7 mg), sodium chloride (9 mg), sodium citrate dihydrate (7.35 mg), and Water for Injection, USP. The pH is 6.5.

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