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Critical Pharmaceuticals has developed two proprietary drug delivery technologies - CriticalSorb and CriticalMix.
CriticalSorb™ Absorption Promoter Technology
CriticalSorb has the potential to provide a viable alternative to injection for a wide variety of drugs. CriticalSorb is a novel absorption promoter for the nasal delivery of biologics and other challenging drugs. The absorption promoter is a pharmaceutically acceptable excipient approved by the FDA as generally regarded as safe (GRAS). It has a drug master file (DMF), and is used in currently marketed products as a solubility enhancer for intravenous and oral administration. In preclinical toxicology studies, CriticalSorb has been found to be nontoxic and not irritating to the skin or eyes and was well tolerated by the nasal mucosa in acute, 14 day and 6 month repeated dose chronic toxicity studies. Furthermore it is not mutagenic to bacteria, mammalian cells and mammals, and no developmental toxicity or teratogenicity has been found. Using conventional manufacturing technologies and delivery devices, possible formulation presentations include liquid nasal sprays or powders for nasal administration.
Critical Pharmaceuticals has used the technology to develop CP024, a nasal growth hormone product in Phase 1 clinical development, but also with risperidone (a small molecule anti‐psychotic), insulin (a small protein for the treatment of diabetes) and two partner programs with novel peptide drugs. The bioavailability of intranasal insulin using CriticalSorb is approximately 100% relative to subcutaneous injection compared to <1% without CriticalSorbTM. Furthermore, the absorbed insulin exerts a pharmacodynamic effect lowering blood glucose by a similar amount to that of the subcutaneous injection.
Clinical proof of concept has been established for CP024 and the CriticalSorb technology. In a Phase 1 clinical trial, CP024 was shown to be well tolerated and able to induce insulin‐like growth factor 1 (IGF‐1) to the same levels as a subcutaneous injection of the marketed product. IGF‐1 is the main mediator of hGH activity in the body and a clinically relevant indicator of bioactivity.
Key properties of CriticalSorb™ are:
 A pharmaceutically acceptable excipient (GRAS) used in marketed products for intravenous and oral administration
A Drug Master File is available.
Preclinical tox studies have shown CriticalSorb™ to be non-toxic, with no irritation to the skin or eyes or nasal mucosa.
Available as liquid or powder formulations.
Promotes absorption of peptides and proteins such as insulin (~6kDa) and human growth hormone (22kDa) across the nasal mucosa in preclinical studies with exceptionally high bioavailabilities.
Generally applicable to all drugs e.g. small molecules, proteins, peptides, DNA.
Protected by pending patents worldwide.
CriticalMix™ Injectable Sustained Release Technology
Critical Pharmaceuticals has developed CriticalMix as a one‐step, solvent-free process that uses supercritical carbon dioxide to facilitate mixing of a therapeutic and a biodegradable polymer to generate drug-loaded controlled‐release formulations. Supercritical carbon dioxide (scCO2) is formed when carbon dioxide (CO2) exceeds its thermodynamic critical point i.e. is at or above its critical temperature and pressure. It has the unique ability to diffuse through solids and to plasticize polymers at low temperatures and pressures making it an excellent alternative to organic solvents that can irreversibly damage the biologic and leave toxic solvent residues.
In the CriticalMix process, the desired polymer / polymer mix and the biologic are placed in a high-pressure chamber and filled with CO2 under pressure resulting in the formation of scCO2. The scCO2 acts as a plasticizing agent and the polymer is then homogeneously mixed with the required biologic using a rotor blade situated within the chamber. The resulting liquefied mixture is then rapidly released through a nozzle causing rapid depressurization and thus solidification resulting in a fine spray of drug-loaded microparticles. Critical Pharmaceuticals uses a range of FDA approved polymers such as PLGA and PLA in novel combinations with a selection of plasticizers and solubilizers such as PEG, Poloxamers and PEGylated derivatives. All of the materials have GRAS status and are widely used in marketed pharmaceutical products and devices. The final sustained release microparticle products are injected through a 25G fine gauge needle. Critical Pharmaceuticals has amassed a wealth of in vitro and in vivo data with CriticalMix demonstrating that by modifying the polymer mixes in the formulation a variety of release profiles are achievable with release controllable from weeks to months. In addition, the technology has been validated with a wide variety of biological therapeutics and has been shown to not significantly change the activity of over 30 drugs tested. A variety of analytical techniques have been used to demonstrate that CriticalMix has no effect on the primary, secondary or tertiary protein structure (e.g. no aggregation or degradation). Critical Pharmaceuticals has developed it’s proprietary supercritical fluid processing equipment to give it a robust capability at both laboratory and GMP manufacturing scale suitable for aseptic operation at a contract manufacturing organisation and the production of sterile batches for human clinical trials. Scale up of the process has not altered the in vitro or in vivo characteristics of the microparticle formulations. Critical Pharmaceuticals has used the CriticalMix technology to develop CP016 a long acting formulation of hGH and has established preclinical proof of concept in a non‐human primate pharmacokinetic and pharmacodynamic study.
Key properties of CriticalMix™ are:
The drug is not chemically modified and the drug activity, stability, safety and distribution in the body are unchanged.
The CriticalMix process operates at ambient temperatures, allowing termperature sensitive molecules such as proteins and peptides to be encapsulated wihtout any degradation.
A wide range of regulatory approved polymers may be used.
A one-step process where 100% of the drug is encapsulated.
The CriticalMix process is entirely solvent free so there are no solvent residue concerns and you can achieve savings on financial and environmental costs associated with solvent disposal.
The therapeutic plasma levels can be maintained for days to weeks / months following a single injection.
Protected by granted and pending patents.
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