Technology overview
CellInject™ Technology
CellInject™ is a trade name of proprietary patented* technology and composition of Solid Lipid Particle (SLN).
CellInject™ is constructed to transport API** into cells.
CellInject™ is constructed to transport API** into cells.
* WO2019116062
** active pharmaceutical ingredient
** active pharmaceutical ingredient
Fate of the CellInject™ Technology particle in the human body
Constant and site independent API release
A. Common case: The particle starts releasing the active pharmaceutical ingredient (API) as soon as it enters into contact with the body fluids. The delivery is constant and follows a specific kinetic model; it is independent of the particle localization or ability to entering the cells.
Solely In-cell API release
B. The API is dispersed within the insoluble nonporous, lipase resistant solid lipid matrix. No release takes place within the body fluids, e.g. CellInject™ is stable in gastro-intestinal juice, saliva, hepatic lipase. Due to its high affinity to lipid membranes and its nano-dimension, the particle flawlessly enters the cell, where undergoes metabolism and erosion, ending up with API release. In case digestion does not happen, the particle can exit the cell by diffusion in the interstitial spaces, where again to “switch-off” the API release until the next cell internalization. The particles can pass through many cell layers switching on and off the API release. This sequenced delivery secures high API concentration within the target cells, and null extracellular release***. Such API saturation in only the target cells but not the outer spaces gives the opportunity the therapeutic doses to be significantly reduced.
***Such an approach is best applicable to API with intracellular mechanism of action. However, surprisingly in our preclinical and clinical experiments it reached therapeutic levels at extremely low dose levels (20x and lower) APIs with extracellular mechanism of action (Loratadine, antihistamine; Xylometazoline, alfa mimetic decongestant).
Due to its unique patent pending composition, based on carnauba, tocotrienols, and proper choice of surfactants and PIT (Phase Inversion Technique) technology, small particles of 20-35 mn are obtained with very narrow size range. The method of production is green, simple, fast, reproducible, non-expensive, and uses only standard equipment for production of dispersion systems (e.g. thermostated reactor). It doesn’t require high-shear homogenization, high-pressure homogenization, ultrasonication, nor organic solvents.
What does CellInject™ stand for
CellInject™ has been developed as the first ever intracell targeted carrier to encapsulate and transport API in an intact state - unchanged and locked (no drug release) through the body liquids such as gastrointestinal fluids, mucus linings, interstitial liquid, secretions and any other watery fluids to the target tissues, organs and cells.
How does it work
CellInject™ is the first ever lipid particulate system constructed to transport API to target cells where to pass through the intracellular metabolite paths ending up with the intact API released. The carrier and its metabolites are biocompatible and non-toxic.
CellIniject™ Technology ensures exceptional combination of particle properties:
- not releasing the encapsulated drug even in the presence of lipases
- undetectable by the immune system as an antigen
- it doesn’t form “protein corona”1 with the body soluble proteins
This way the therapeutic dose of the active ingredient can be dramatically reduced.
What are the applications of CellInject™
CellInject™ is constructed to deliver intracellularly the API. CellInject™ is compatible with most of the lipophilic API in their free non-salt forms. CellInject™ is especially applicable to substances with low bioavailability, low water solubility, low therapeutic window, short lifetime and those which mechanism of action is intracellular. While itself sustaining a high bioavailability CellInject™ is able to freely and safely travel through the mucous layers and body tissues, including blood-brain barrier. It is applicable to every situation requiring cell therapy, including Oncology therapies, Diabetes, CNS disorders, Alzheimer’s disease, Parkinson’s disease, Schizophrenia, Multiple Sclerosis, Cardiovascular disease, Allergies, Asthma, etc.
CellInject™ is applicable as a carrier of diagnostic agents.
CellInject™ is applicable as a carrier of diagnostic agents.
More about ABOUT SLN
- Solid lipid nanoparticulate systems (SLN) have been originally developed as nontoxic and chemically stable substitute to traditional carriers such as polymeric nanoparticles and liposomes.
- SLN are distinct with their safety, enzyme degradation to nontoxic metabolites, unimpeded travel through cell membranes and other biological barriers.
- SLN consist of a solid lipid core comprising a lipid or mixture of lipids and at least one emulsifier. They are useful for application to many different administration routes: dermal and mucosal, oral, intravenous/parenteral, pulmonary but also ocular, as well as in cosmetics and for non-pharmaceutical use, e.g. in medical devices and nutraceuticals.
- The ability to incorporate drugs into lipid nanocarriers offers a new prototype in drug delivery that leads to the bioavailability enhancement along with control of the rate of active ingredient release and site-specific drug delivery. The lipid matrix of SLN can protect labile active ingredients from hydrolysis and/or oxidation.
1 It is increasingly being accepted that once entered the body, nanoparticles can be recognized by the responsible immune cells as antigens directly or after covering with protein corona. After administration, some nanoparticles can interact with tissue proteins and other molecules. Particle conjugates can be detected by the immune system, evoking a pro-inflammatory response. The protein corona also influences the interactions of particles with the cell membrane. Adsorption of proteins can modify the surface charge and may impart for altered drug targeting/metabolism. [Bogart LK et al. Nanoparticles for Imaging, Sensing, and Therapeutic Intervention. ACS Nano. 2014;8(4):3107-3122. doi:10.1021/nn500962q].
The adsorption of proteins on the surface of nanoparticle is governed by protein–nanoparticle binding affinities as well as protein–protein interactions. The most abundant proteins, albumin and fibrinogen, were found on the surface of many types of nanoparticles. Albumin itself shows affinity to hydrophobic surfaces and polyanions. Also, formation of hard (primary) and soft (secondary) corona is associated with increase in particle diameter hence slowed down ability for diffusion and entering cells. [M. Rahman et al., Protein-Nanoparticle Interactions, Springer Series in Biophysics 15, DOI 10.1007/978-3-642-37555-2_2, © Springer-Verlag Berlin Heidelberg 2013].
2 Cell targeting of active pharmaceutical ingredients classified as substrates of the P-glycoprotein (P-gp).
P-gp is one of the first members of the ATP-binding cassette (ABC). The role of P-gp is likely to protect cells from toxic compounds, preventing them to enter the cytosol and extrude them to the exterior. P-gp is expressed on the epithelial cells lining the colon, small intestine, pancreatic ductules, bile ductules, kidney proximal tubules, adrenal gland, respiratory ways, placenta. It is also located in the endothelial cells of the blood brain barrier. The transporter is overexpressed on the surface of many neoplastic cells and restricts cell entry of many of the known antineoplastic drugs. P-gp has broad poly-specificity, recognizing hundreds of compounds or drugs as small as 330 up to 4000 Da As the substrate binding pocket sits inside the cellular membrane and needs to be accessed by distribution into the lipid bilayer, the lipophilic and amphiphilic nature of the substrates is to be expected. P-gp can eject a wide range of structurally diverse compounds out of the cells, including anticancer agents, immunosuppressants, steroid hormones, calcium channel blockers, beta-adrenoreceptor blockers, cardiac glycosides, among others. Less permeable drugs (weak substrates) may also undergo a substantial extrusion. Thus, it contributes greatly in the extrusion of many drugs penetrated from particular sites of administration (e.g. the intestinal lumen and other mucosal tissues). P-gp is also responsible for enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. Therefore, P-gp can potentially reduce the absorption and oral bioavailability and decrease the retention time of a number of drugs. Additionally, it has a role in limiting cellular uptake of drugs from blood circulation into the brain while being present in the BBB.
The P-gp efflux transporter located within the blood-brain barrier restricts the uptake of drugs and other molecules within the CNS; drug efflux is a common mechanism of resistance in microorganisms; P-gp is overexpressed on the surface of cancer cells and prevents drug accumulation inside the tumor, extruding it before can reach the intended target.
The adsorption of proteins on the surface of nanoparticle is governed by protein–nanoparticle binding affinities as well as protein–protein interactions. The most abundant proteins, albumin and fibrinogen, were found on the surface of many types of nanoparticles. Albumin itself shows affinity to hydrophobic surfaces and polyanions. Also, formation of hard (primary) and soft (secondary) corona is associated with increase in particle diameter hence slowed down ability for diffusion and entering cells. [M. Rahman et al., Protein-Nanoparticle Interactions, Springer Series in Biophysics 15, DOI 10.1007/978-3-642-37555-2_2, © Springer-Verlag Berlin Heidelberg 2013].
2 Cell targeting of active pharmaceutical ingredients classified as substrates of the P-glycoprotein (P-gp).
P-gp is one of the first members of the ATP-binding cassette (ABC). The role of P-gp is likely to protect cells from toxic compounds, preventing them to enter the cytosol and extrude them to the exterior. P-gp is expressed on the epithelial cells lining the colon, small intestine, pancreatic ductules, bile ductules, kidney proximal tubules, adrenal gland, respiratory ways, placenta. It is also located in the endothelial cells of the blood brain barrier. The transporter is overexpressed on the surface of many neoplastic cells and restricts cell entry of many of the known antineoplastic drugs. P-gp has broad poly-specificity, recognizing hundreds of compounds or drugs as small as 330 up to 4000 Da As the substrate binding pocket sits inside the cellular membrane and needs to be accessed by distribution into the lipid bilayer, the lipophilic and amphiphilic nature of the substrates is to be expected. P-gp can eject a wide range of structurally diverse compounds out of the cells, including anticancer agents, immunosuppressants, steroid hormones, calcium channel blockers, beta-adrenoreceptor blockers, cardiac glycosides, among others. Less permeable drugs (weak substrates) may also undergo a substantial extrusion. Thus, it contributes greatly in the extrusion of many drugs penetrated from particular sites of administration (e.g. the intestinal lumen and other mucosal tissues). P-gp is also responsible for enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. Therefore, P-gp can potentially reduce the absorption and oral bioavailability and decrease the retention time of a number of drugs. Additionally, it has a role in limiting cellular uptake of drugs from blood circulation into the brain while being present in the BBB.
The P-gp efflux transporter located within the blood-brain barrier restricts the uptake of drugs and other molecules within the CNS; drug efflux is a common mechanism of resistance in microorganisms; P-gp is overexpressed on the surface of cancer cells and prevents drug accumulation inside the tumor, extruding it before can reach the intended target.