Witepsol W35 is a lipid-based excipient primarily used in the pharmaceutical industry for the production of suppositories and pessaries. Derived from a blend of saturated fatty acid triglycerides, Witepsol W35 is known for its body-temperature melting properties, chemical stability, and ease of processing. It is especially valued for its controlled melting point, allowing for efficient and uniform release of active ingredients.

Chemical Composition and Structure

Witepsol W35 consists of saturated triglycerides, typically derived from vegetable or synthetic sources. It is a complex mixture of medium and long-chain fatty acids such as stearic acid and palmitic acid, esterified with glycerol. This composition gives it low-temperature melting properties, enabling the product to solidify quickly and release active ingredients at body temperature.

The name describes the structure of the molecule

"Witepsol" is the trade name for a family of suppository bases produced by Hüls (now part of Evonik). "W35" is a specific designation identifying a particular formula or composition within this series.

Description of raw materials used in production

• Saturated fatty acid esters: Lipid components that provide the solid base of the suppository.
• Triglycerides: Act as plasticizers and modulate the physical properties of the base.

The exact composition and proportions of raw materials vary depending on the specific Witepsol formula.

Production Process

Witepsol W35 is produced by esterifying glycerol with saturated fatty acids derived from either vegetable or synthetic sources. The process is carefully controlled to ensure the purity, consistency, and quality of the final product. Once the triglyceride mixture is obtained, it is purified and solidified to produce the ready-to-use pharmaceutical-grade form. 

Please note that producing Witepsol W35 is not a "synthesis" in the traditional sense but rather a blending and modulating of the physical properties of lipids.

• Selection of Raw Materials: The main ingredients for producing Witepsol W35 include refined vegetable oils, such as palm oil, coconut oil, and other sources of vegetable fat. These ingredients are selected for their physical and chemical properties.

• Hydrogenation: The selected vegetable oils undergo a hydrogenation process, where hydrogen is added to the oils in the presence of a catalyst. This process transforms the unsaturated fatty acids present in the oils into saturated fatty acids, improving the stability and consistency of the final product.

• Esterification: After hydrogenation, the fatty acids are combined with glycerol in an esterification process. This is done by heating the fatty acids and glycerol together in the presence of an acid catalyst, promoting the formation of esters.

• Refining: The resulting product is refined to remove any impurities and ensure quality. This may include processes such as filtration, bleaching, and deodorization.

• Quality Control and Packaging: Finally, Witepsol W35 undergoes quality control checks to verify its purity, stability, and functional properties. After analysis, it is packaged for distribution and use in pharmaceutical formulations.

The quantities normally used are 1.1275 g for 125 mg suppositories, 1.15 g for 250 mg oral medicines (1).

Applications

• Pharmaceutical Industry: Witepsol W35 is primarily used as an excipient in the production of suppositories and pessaries. Its melting point close to body temperature ensures controlled and uniform release of active ingredients.

• Drug Delivery Systems: Used as a base in solid drug formulations, it enhances the stability and bioavailability of active ingredients in rectal or vaginal drug delivery systems.

• Solid Cosmetics: In some cosmetic formulations, it can be used as a solid base for products such as balms or sticks.

Safety

The only problem with this grease is its oxidation when left in contact with air for a long time. It is therefore necessary to use the drugs that contain it in a short time  and check the expiration date.

Safety in Use
Witepsol W35 is considered safe for pharmaceutical use and is not known to cause irritation or adverse reactions. It is inert and non-reactive with most active pharmaceutical ingredients, making it an ideal excipient for suppositories. It is well tolerated and does not cause significant side effects.

Allergic Reactions
Allergic reactions to Witepsol W35 are extremely rare due to its inert lipid nature and wide compatibility with drugs. However, as with any excipient, preliminary testing is advised for formulations intended for patients with sensitive skin or known allergies.

Toxicity and Carcinogenicity
It has been extensively tested for pharmaceutical use and approved by major regulatory authorities for safety and efficacy.

Environmental Considerations
Being derived from vegetable or synthetic sources, Witepsol W35 is biodegradable and poses no significant environmental risks. However, its industrial production requires energy resources, and the sustainable use of plant-derived materials can help reduce its environmental footprint.

Regulatory Status
Witepsol W35 is approved for pharmaceutical use by major regulatory authorities, including the European Union and the Food and Drug Administration (FDA) in the United States. It is widely used in a range of pharmaceutical formulations.

Studies

Sznitowska M, Janicki S, Gajewska M, Kulik M. Investigation of diazepam lipospheres based on Witepsol and lecithin intended for oral or rectal delivery. Acta Pol Pharm. 2000 Jan-Feb;57(1):61-4.

Abstract. Diazepam was incorporated in lipospheres prepared by high pressure homogenization of melted Witepsol (10%) dispersed in aqueous lecithin (2.4%). Diazepam content was 0.4% and more than 98% of the dose was found to be encapsulated in the lipospheres. Although the initial mean particle size was 0.3 micron, the liposhperes agglomerated during storage and this phenomenon was not eliminated by increasing lecithin concentration to 4% or incorporation of oleic acid (0.1%) and co-surfactants, polysorbate 80 (0.5%) or poloxamer (up to 6%). The formulation was not able to mask effectively bitter taste of diazepam, even when lipids of higher melting temperature, namely glyceryl tripalmitate or stearic acid, were introduced.

Hosny EA, Al-Shora HI, Elmazar MM. Effect of different bile salts on the relative hypoglycemia of witepsol W35 suppositories containing insulin in diabetic Beagle dogs. Drug Dev Ind Pharm. 2001 Sep;27(8):837-45. doi: 10.1081/ddc-100107248. 

Abstract. Insulin suppositories were formulated using Witepsol W35 as a base to investigate the effect of various bile salts/acids on the plasma glucose concentration of diabetic beagle dogs. Comparison of the effect of these formulations was made with that produced by insulin subcutaneous injections. Of the bile salts/acids studied, incorporation of 100 mg of deoxycholic acid (DCA), sodium cholate (NaC), or sodium deoxycholate (NaDC) with insulin (10 U/Kg) showed that suppositories containing NaDC produced the highest area under the curve (AUC) and relative hypoglycemia (RH) of 290 +/- 83 mg%h and 28% +/- 8.1%, respectively. To study the optimum amount of NaDC in insulin suppositories to produce the highest RH, 50-200 mg/suppository were used, and we found that 150 mg NaDC produced 35% +/- 13% RH. We also studied the influence of different doses of insulin (5-20 U/kg) in the presence of NaDC (100 mg). It was found that increase of the insulin dose was accompanied by an increase in AUC and maximum reduction in plasma glucose level Cmax. A combination of NaDC (100 mg) and NaC (50 mg) produced an AUC of 252 +/- 13mg%h and an RH of 49% +/- 2.6%, which were higher than produced by either of its individual components (NaC 50 mg or NaDC 100 mg) when used alone or when compared with an equivalent amount of NaDC (150 mg). When the effect of sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC) was studied, it was found that an insulin suppository containing 100 mg of either NaTC or NaTDC produced an RH equivalent to that produced previouslY with a mixture of NaDC (100 mg) and NaC (50 mg). On the other hand, NaC (50 mg) did not improve the hypoglycemic effect of NaTC any further. In conclusion, a relative hYpoglycemia of about 50% can be reached using insulin suppositories containing Witepsol W35 as a base and NaDC plus NaC (100 mg plus 50 mg, respectively), NaTDC (100mg), or NaTC (100 mg) as rectal absorption enhancers of insulin. A desirable hypoglycemia, expressed as Cmax, and/or AUC can be reached by adjusting the insulin dose in the formulation according to the degree of hyperglycemia.

Al-Kassas R, Donnelly RF, McCarron PA. Aminolevulinic acid-loaded Witepsol microparticles manufactured using a spray congealing procedure: implications for topical photodynamic therapy. J Pharm Pharmacol. 2009 Sep;61(9):1125-35. doi: 10.1211/jpp/61.09.0001.

Abstract. Objectives: The aim was to enhance aminolevulinic acid (ALA) stability by incorporation into low-melting microparticles prepared using a spray congealing procedure and to evaluate temperature-triggered release, allowing topical bioavailability following melting at skin temperature. Methods: ALA-loaded Witepsol microparticles were prepared using a novel spray congealing technique. Entrapment efficiency was compared with conventional emulsion-based methods and modelled drug release profiles determined using a membrane separation technique. Raised receiver medium temperature was used to determine triggered release. Bioavailability and lipid-mediated enhancement of ALA penetration were determined in excised murine skin.....Conclusions: Spray congealing is superior to the emulsion-based procedures with respect to encapsulation efficiency of ALA in Witepsol matrices, providing temperature-triggered release, enhanced stability and improved penetration of ALA through keratinised skin. These features could improve ALA delivery to superficial lesions as part of photodynamic therapy.

Nepal PR, Han HK, Choi HK. Preparation and in vitro-in vivo evaluation of Witepsol H35 based self-nanoemulsifying drug delivery systems (SNEDDS) of coenzyme Q(10). Eur J Pharm Sci. 2010 Feb 19;39(4):224-32. doi: 10.1016/j.ejps.2009.12.004. Epub 2009 Dec 24. PMID: 20035865.

Iwata M, Komiya S, Nakamura K, Kiuchi M, Andoh N, Hirahara F, Maitani Y, Takayama K. Release property of progesterone from a mixed-base suppository consisting of Witepsol W35 and Witepsol E85. Drug Dev Ind Pharm. 2001 Nov;27(10):1039-45. doi: 10.1081/ddc-100108366. 

Abstract. The mechanism of drug release from progesterone suppositories that consist of two types of hard fat (Witepsol W35 and Witepsol E85) was investigated. The strength, the thermodynamic characteristics, the surface structures, the drug release property, methylene blue penetration into suppositories, and change of surface structure after the dissolution test were employed for detecting characteristics of progesterone suppositories. The formulation with a mixing ratio of Witepsol W35 and Witepsol E85 at a 1:1 ratio showed the maximum strength value. The peak temperature of the suppositories showed a tendency to increase with increases in the ratio of Witepsol E85. The maximum height of the profiles measured with laser microscopy, from 20.8 microm to 29.2 microm, reached a maximum after 3 h of the dissolution test. When the suppositories were immersed in pH 7.4 phosphate buffer containing 0.5% methylene blue at 37 degrees C, the penetrating area increased with time. The weight of the suppositories also increased with time. According to these findings, it was suggested that the release of drug from a mixed type of suppository containing progesterone was via the matrix and pores.

Campos DA, Madureira AR, Gomes AM, Sarmento B, Pintado MM. Optimization of the production of solid Witepsol nanoparticles loaded with rosmarinic acid. Colloids Surf B Biointerfaces. 2014 Mar 1;115:109-17. doi: 10.1016/j.colsurfb.2013.10.035. Epub 2013 Nov 21. PMID: 24413308.

References_____________________________________________________

(1) Ba B, Gaudin K, Désiré A, Phoeung T, Langlois MH, Behl CR, Unowsky J, Patel IH, Malick AW, Gomes M, White N, Kauss T. Ceftriaxone Absorption Enhancement for Noninvasive Administration as an Alternative to Injectable Solutions. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01170-18. doi: 10.1128/AAC.01170-18. PMID: 30348664; PMCID: PMC6256799.