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.

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.

Recent News - Lawsuits

On November 29, 2023, Regeneron Pharmaceuticals, Inc. filed a Compliant against Formycon AG (“Formycon”) in the U.S. District Court for the Northern District of West Virginia, alleging infringement of 39 patents under the BPCIA based on Formycon’s submission of an aBLA for FYB203, a proposed biosimilar of EYLEA (aflibercept).  According to the news, this was the fourth infringement suit under the BPCIA concerning a proposed biosimilar of EYLEA, after Regeneron sued Mylan (August 2, 2022), Celltrion (November 8, 2023), and Samsung Bioepis (November 22, 2023).

Regeneron states that the use of Formycon's FYB203 will infringe multiple related to the methods of adminstering aflibercept, stable formulations of aflibercept, and its manufacturing process, totally 3 groups. And here are the 3 groups of patents: 

8 method of treatment patents: U.S. Patent Nos. 9,254,338; 10,130,681; 10,828,345; 10,888,601; 11,253,572; 11,559,564; 11,707,506; and 11,769,597.

4 formulation patents: U.S. Patent Nos. 10,464,992; 11,066,458; 11,084,865; and 11,732,024.

27 manufacturing process patents:  U.S. Patent Nos. 7,070,959; 7,771,997; 9,222,106; 9,562,238; 9,816,110; 9,932,605; 10,415,055; 10,669,594; 10,927,342; 11,053,280; 11,104,715; 11,174,283; 11,268,109; 11,299,532; 11,306,135; 11,312,936; 11,332,771; 11,472,861; 11,485,770; 11,535,663; 11,542,317; 11,548,932; 11,549,154; 11,555,176; 11,680,930; 11,753,459 and 11,788,102.

Here is the list of Purple Book Patents for Eylea (aflibercept)

Reference: 

Product Insert,

Kristin M. Beale, Regeneron sues Formycon AG for proposed biosimilar of EYLEA in West Virginia District Court, Bio Molecule Watch, December 11, 2023. Assessed on Feb 06, 2024.

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.