- Do you have oral bioavailability enhancement for low soluble drugs?
- How many low soluble molecules did you test with their technology so far?
- What is the typical drug load for small molecules?
- Do you have experience with drying the Siosomes® powder or is this a liquid dosage form?
- Do you have any safety data for Siosomes® molecules for the oral route?
- How do Siosomes® respond to the RES with respect to the size?
- Is the Silane material GRAS listed (approved pharma exipient)?
1. Do you have oral bioavailability enhancement for low soluble drugs?
We do not have data on the oral bioavailability enhancement for low soluble drugs.
Our main strategy for the application of the technology using Siosomes® was the development of intravenous solutions with anti-cancer and anti-viral drugs. The objectives are for optimal drug delivery and targeting of the anti-cancer agents. A number of animal studies in rats and rabbits have been performed using e.g. encapsulated Cis-oxoplatin (low soluble) in pharmacokinetic and tissue distribution studies. We were able to demonstrate slow release in the above applications hence we are confident that we should be able to demonstrate the same in oral application.
If a client is interested in the development of Siosome-Drug X for oral application, SIOGEN could offer the client a co-development program for this specific low soluble compound(s). In addition, we have the experience to develop and perform the animal studies (bioavailability, tissue distributions,… etc) if the client requires these activities.
2. How many low soluble molecules did you test with their technology so far?
The following low soluble active agents have been encapsulated in Siosomes®:
Dithranol (practically insoluble in water). In addition it becomes orange-red on exposure to air. Dithranol as topical formulation is used for the treatment of psoriasis.
Salicylic acid Solubility in water wt % 0.20 (20 ºC). Nifedipine - Practically insoluble in water and solutions are extremely light sensitive
Cis-oxoplatin - Very low solubility- 1g in about 1000ml water
Arsenic Trioxide (As203) -Sparingly and extremely slowly soluble in water.
3. What is the typical drug load for small molecules?
The following encapsulated small molecules active agents have been prepared as “Lyophilisate” in injection vials:
| Active agent “small molecules” | Amount of active agents (mg) | Amount of Siosomes® (mg) |
| 1. Cis-oxoplatin | 5 | 10 |
| 2. Arsenic Trioxide | 0.8-1 | 10 |
| 3. Sodium Meta-arsenite | 10.08 | 10 |
| 4. Foscarnet | 27 | 10 |
The above mentioned concentrations per vial have been selected based on the design of the in-vitro and in-vivo studies in animals and the requested amounts of the API’s, NCE’s for injections. The encapsulation efficiency of each active agent depends on the physical chemical properties of the API’s and the Silanes/sugar-Silanes to be used for the preparation of the Siosomes®.
Within the validation of the encapsulation procedures, a number of the critical parameters will be investigated e.g.
- physical chemical properties of the API e.g. solubility, stability…
- encapsulation efficiency
- pharmaceutical formulation and route of administration e.g. oral.IV, IP…
- in-vivo release profile
The most recent results on the Silane concentrations are in the range of 0.5-1.5mg Silane per 6ml vials for injections. These concentrations are considered as low. Based on our experience, we could adjust the ration API/mg Siosomes® to meet the required safety, bioavailability and release profile of the API.
Each API-Siosomes®-Product could be delivered as lyophilised powder for use in oral formulations e.g. immediate release capsules and/or sustained release capsules and/or oral solutions.
4. Do you have experience with drying the Siosomes® powder or is this a liquid dosage form?
The following stability investigations have been performed:
Stability of the Siosomes®-API’s emulsions prior to the lyophilisation were stable for at least 10 days at 2-6 ºC. Stability of the Siosome®s-API’s emulsions after the reconstitution of the lyophilisate powder with sterile deionised water for injection. The emulsions of the Siosomes® were stable for at least 10days at 2-6 ºC.
The lyophilisate powder of Foscarnet, Cis-oxoplatin, Arsenic Trioxide, Sodium Meta-arsenite are stable for longer than 2 years at 2-6 ºC. No sign of instability have been observed (colour change, degradation). The stability tests according to the standard procedures (particle size after reconstitution, content of the API) could be performed in the next future.
5. Do you have any safety data for Siosomes® molecules for the oral route?
The following toxicity, pharmacological investigations have been performed using the following Silanes:
We do not have safety data generated specifically using Siosomes® molecules for the oral route. The main objective of the R&D program on Silanes and Siosomes® was to develop intravenous formulations for anti-cancer and anti-viral drugs. A number of animal studies have been performed using Siosomes® encapsulated active agents as anti-cancer drugs.
In addition, the following investigations on toxicity and safety have been performed using the different Silanes and sugar-Silanes. Based on the significant advantages of the enormous diversity of the patent protected organo-silicon compounds, a large number of Siosomes® representing the different classes of compounds (Silanes, sugar-Silanes… etc) have been synthesized and investigated for their pharmacological and toxicological activities.
As a result of the many years of investigations, the following was concluded:
A number of Siosomes® have shown inert properties with no toxicological/ pharmacological activity. The results of the cytotoxicity tests, vitality tests and morphological controls using all aorta endothelium cell lines BKEZ-7 have shown that the following Silanes have no cytotoxicity and is non-toxic at the given concentrations:
NO |
TEST COMPOUND | IC50-VALUE (mM) | CRITICAL TOXICITY |
1 |
Di(dodecanoyloxy)diphenylsilan | 0.036 | none |
2 |
Di(decanoyloxy)diphenylsilan | 0.014 | none |
3 |
Di(octadecanoyloxy)diphenylsilan | 0.084 | none |
4 |
Di(octanoyloxy)diphenylsilan | >0.02 | none |
5 |
Di(tetradecanoyloxy)diphenylsilan | 0.046 | none |
6 |
Di(dodecanoyloxy)dimethylsilan | 0.129 | none |
7 |
Di(octadecanoyloxy)dimethylsilan | 0.495 | none |
8 |
Di(tetradecanoyloxy)dimethylsilan | 0.110 | none |
6. How do Siosomes® respond to the RES with respect to the size?
To evade the RES, the size of a nanoparticle needs to be less than 150 nm. We have succesfully created several batches of Siosomes® below 150 nm with a 10 % distribution range. The Siosomes® can be GMP manufactured within the size range of 40nm -1500nm with 10% size distribution.
Its known that sugar molecules are able to camouflage nanoparticles from the immune system and to play a part in cell to cell interaction. Our 4th generation Siosomes® focuses on sugar organosilicon compounds. This means the surface of Siosomes® are with sugar molecules hence have potentially the ability to evade the immune system.
7. Is the Silane material GRAS listed (approved pharma exipient)?
The Silanes are not approved pharma excipient. SIOGEN Biotech are proprietary owners of the Silane technology and its manufacturing processes. We aim to GRAS list our Inert Siosomes® in the near future.
We are qualifying a number of the Silanes/ Sugar Silanes, which will have the following properties as “API’s”:
- Anti – Cancer Activities
- Anti – Viral Activities
- Anti – Bacterial Activities
- Immune – Stimulating Agents
Silicon exists in the human body (average of 5-10 g) and they have been shown to play a role in the growth of of hair, nails, bones, cartilage and connective tissues. (Anal. Biochem. 2005 Feb 1; 337(1): 130-5). There are also silicon based compounds that are GRAS listed (i.e. silicon dioxide).
SIOGEN Biotech benchmarks its Siosomes® technology with Liposomes and there are significant amount of data on Liposomes for the past 35 years on efficacy, toxicity and delivery. Siosomes® have been measured against Liposomes and we are clear of our competitive advantages.
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