 KG, Glockengiesserwall 3, 20095 Hamburg, Germany. WITEPSOL H grades are hard fats with a low hydroxyl value of max. 15 and comprise mainly triglycerides with proportions of max. 15% of diglycerides and max. 1% of monoglycerides. H12 has a melting point of about 32-33.5° C. and a hydroxyl value of 5-15 mg KOH/g WITEPSOL W grades are hard fats with hydroxyl values between 20-50. They comprise a mixture of 65-80% of triglycerides, 10-35% of diglycerides and 1-5% of monoglycerides. W45 has a melting point of about 33-35.5° C. and a hydroxyl value of 40-50 mg KOH/g.
PEG-Dow Chemical offers several polyethylene glycol compounds which are water soluble and have various molecular weights known as Carbowax® Sentry. The preferred PEG selected for the comparative study was PEG 1450 also referred to as Carbowax® Sentry1450 as described below with a molecular weight range of 1305-1595.
Molecular Average Number Melting at Solubility in Weight of Repeating CTFA Density Density Freezing Water at Viscosity Products Form Range Oxyethylene units Nomenclature (20° C.) (60° C.) Range 20° C., % by wt at 100° C.
Suppocire AIML®—Semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and a phospholipid additive (lecithin) with a low hydroxyl value available from Gattefossé with headquarters in Saint-Priest, Lyon.
Contrary to initial expectations that MBK in a fatty acid base would provide superior transport directly through the cell membrane it was discovered that water soluble polar excipients appear to provide better transport of the CaNa2EDTA and are therefore expected to provide elevated concentrations of the EDTA in the blood for superior heavy metal chelation. In particular Suppocire AIML and Witepsol H12, were the most effective, with Witepsol W45 being effective to a lesser extent. These compounds are all glyceride based compounds. PEG 1450, even though it is water soluble, was beneficial but to a less effective extent. MBK provided an EDTA transport of less than about 8% of the two most effective excipients and only about 14% of the transport provided by PEG 1450.
A typical rectal suppository is a conical or torpedo shaped item about 2-3 centimeters in length. Suppositories for adults weigh about 2-3 grams each; children suppositories weigh about 1-2 grams each. The typical carriers used are waxy materials in which the active ingredients have been dissolved or suspended. The carrier can comprise, but is not limited to, glycerin, glyceryl monopalmitate, glyceryl monostearate, hydrogenated coconut oil fatty acids, cocoa butter, and hydrogenated palm kernel oil fatty acids.
The same result could be achieved by allowing the drug to dissolve in the body fluid and adjusting the pH. However, this could cause precipitation and loss of bioavailability as discussed above. As a result, the direct transfer of the non-ionic drug from the excipient-containing suppository to the absorbing cells allows the correct and advantageous optimization and delivery of hydrophilic anionic drugs.
The above process bypasses the traditional concept of solvation of the drug into the surrounding body fluid and is dependent on the contact of the CaNa2EDTA-MBK containing composition directly with the absorbing cells. Mass transfer of the drug through the excipient to the cell membrane is assumed to occur through diffusion in light of the small volume of rectal fluid present (about 3 ml with a pH of about 7.5) compared to the volume of a typical suppository (also about 3 ml for adults).
This composition disclosed herein can be used to better define molecular models; better design and choose excipients that interact with absorbing cells and exclude water; and re-design PAMPA and CACO-2 analyses to test permeability of a drug in a hydrophobic medium versus an aqueous medium. Other dosage forms that will benefit from this new understanding of hydrophilic drug absorbance are identified herein.
In addition, solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (e.g., gums, zanthans, cellulosics and sugars), humectants (e.g., sorbitol), solubilizers (e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives (e.g. parabens) and antioxidants (e.g., vitamins E and C, and ascorbic acid), anti-caking agents, coating agents, and chelating agents other than EDTA.
MBK was used in prior work and considered to allow fairly good absorption of the drug. However, the MBK was in a fatty base and the addition of methyl cellulose does not appear to change its functional characteristics. As the fatty base slowly melts at body temperature (melting point between 30 and 37 degrees), it may not release the drug rapidly for good absorption. In fact, some of the drug may be so intimately bound to the base that it does not release at all.
In contrast, PEG is a completely water soluble base and melts and dissolves to release the drug readily. However, the drug is poorly permeable and, although released in the rectal fluid, may not be readily absorbed.
The Witepsol and Suppocire bases are triglycerides (fatty bases) with some mono- and di-glycerides which act as emulsifying agents. Thus at least some of the fatty base is emulsified. The emulsion contains water and oil in intimate contact and in this physical form, the drug is allowed to permeate the rectal issues. While the exact mechanism of permeation enhancement is not known, it is believed that the emulsion allows and intimate contact of oil and water and provides the best environment for the absorption of the drug.
PEG provided a better bioavailability than the MBK composition because the PEG is hydrophilic and does not retard release of the drug while the MBK hydrophobic base does retard release. The Witepsol and Suppocire bases form emulsions, in part, thus facilitating absorption. Witepsol W45 displayed better bioavailability than PEG, and Witepsol H12 showed better bioavailability than the W45 grade. The Suppocire product contains lecithin as an emulsifying agent (in addition to mono- and di-glycerides), thus providing a similar effect.
Although Suppocire displayed slightly lower bioavailability than Witepsol H12, the relative standard deviation value of the bioavailability data from individual subjects (RSD) receiving Suppocire were significantly lower for this incipient.
To further enhance the solubilization, absorption and transport of the EDTA compound, the CaNa2 EDTA or any alternative EDTA compounds that are used, can be micronized or nanosized. Traditional micronization techniques are based on friction to reduce particle size to a few microns in diameter. Nano-sized particles are a few nanometers in size. Such methods include milling, bashing and grinding. Alternatively the EDTA salts can initially be crystallized as micron-sized or nano-sized crystals. Published literature has shown that nanoparticles, because of their size, can increase the potential for the nanosized material to crossing the various biological barriers within the body, in particular the blood brain and can allow access into the cell and various cellular compartments including the nucleus.
While the above described products are suppositories, the formulations provided above can be utilized for transdermal delivery of the EDTA compounds or delivery through other mucus membranes such as buccal contacting delivery systems.
iii. a carrier comprising one or more of glycerin, glyceryl monopalmitate, glyceryl monostearate, hydrogenated coconut oil fatty acids, cocoa butter, and fatty acids.
2. The suppository of claim 1 wherein the hydrophobic excipients are glyceride based compounds and form an emulsion with calcium disodium ethylenediaminetetraacetate.
3. The suppository of claim 2 include an emulsifying agent.
4. The suppository of claim 3 wherein the hydrophobic excipients are mixtures comprising triglyceride and diglycerides, the diglycerides acting as emulsifying agents.
5. The suppository of claim 1 comprising about 50% of the hydrophobic excipient and about 50% of CaNa2EDTA.
6. The suppository of claim 1 comprising about 100 mg to about 1.2 gm of CaNa2EDTA.
7. The suppository of claim 1 comprising about 600 mg of the hydrophobic excipient and about 600 mg of CaNa2EDTA.
8. The suppository of claim 1 having a length of about 2-3 centimeters and a weight of about 1-2 g.
9. The suppository of claim 3 wherein the hydrophobic excipients comprises triglycerides and the emulsifier is lecithin.
10. The suppository of claim 1 wherein the CaNa2EDTA comprises micron or nanosize particles.
<gh_stars>0
	public static class SwaggerGenerator
	{
		public static async Task Go ()
		{
			var swaggerJson = await "https://api.mobile.azure.com/preview/swagger.json".GetJsonFromUrlAsync ();

			var swaggerJsonObject = JsonObject.Parse (swaggerJson);

			var swaggerJsonArrayObjects = swaggerJsonObject.Object ("paths").ToDictionary (k => k.Key, v => JsonObject.Parse (