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By Maria Carvalho, PharmD, MRPharmS, PhD, Manager of PCCA Science
PCCA’s Research and Development department is committed to developing the most effective, innovative and functional products for the compounding industry. In that spirit, we invest significant time and resources to the study and validation of our technology. Our newest base, Ellage, is no exception. That’s why we are proud and excited to give you an in-depth look at the science behind the first ever anhydrous compounding base developed specifically for the vaginal delivery of medications.
1. The Science behind the Innovation in Ellage
A key innovative property of Ellage is its self-emulsifying drug delivery system, which has the potential to maximize drug solubility and bioavailability. Upon microscopic evaluation, we observed that Ellage developed droplets when mixed with a vaginal fluid simulant (VFS), and these droplets decreased in size between 1–5 minutes of incubation at 98.6° F (37° C). This is the process of self-emulsifying, and we observed it as well in the presence of active pharmaceutical ingredients (APIs) and small amounts of VFS. On the contrary, PCCA Plasticized™ (an anhydrous gel base) did not mix with VFS at all. VersaBase® Cream (an emulsifying cream base) made a homogeneous emulsion, but the size of the droplets remained unchanged.1
Using fluorescence microscopy, we also observed that hydrophilic and lipophilic substances exhibit a different distribution pattern when Ellage is mixed with VFS. Fluorescein sodium (hydrophilic) and curcumin (lipophilic) were evenly distributed in Ellage alone, but when the spontaneous emulsion was created from contact with VFS, the curcumin was encapsulated inside the droplets, whereas the fluorescein sodium remained in the continuous aqueous phase.2
Another key innovative property of Ellage is its advanced mucoadhesion, which has the potential to increase the contact time between the APIs and the vaginal mucosa. We performed in vitro and ex vivo tests on Ellage to evaluate its leakage potential and mucoadhesive properties. We used an over-the-counter (OTC) vaginal moisturizer, which claims to be long-lasting (up to three days), for comparison purposes in these tests. Results from the leakage test show that Ellage alone and in PCCA formulas with amitriptyline 2% and baclofen 2% as well as estriol 0.1% and testosterone 0.1%, respectively, have high retention potential in vitro, superior to the OTC product.3
Likewise, testing on animal vaginal tissues demonstrates that Ellage and the well-established combination of MucoLox™/VersaBase Gel (50:50) exhibit prolonged mucoadhesion, superior to the OTC product. 4 Our bioadhesion testing using a texture analyzer also demonstrates that Ellage has a good bioadhesion profile, similar to MucoLox/VersaBase Gel (50:50) as well as the OTC product.5
The Clinical Significance of the Innovation
For compounding pharmacists, these results are clinically significant because Ellage is expected to exhibit its self-emulsifying properties even in the presence of small amounts of vaginal fluid, such as one would expect with cases of vaginal dryness. In addition, lipophilic APIs are expected to exhibit a slow drug release whereas hydrophilic APIs are expected to exhibit a fast drug release from Ellage.
In clinical practice, custom medications compounded with Ellage are also expected to adhere to the vaginal mucosa for a long period of time, despite the secretion of vaginal fluid, because of its prolonged mucoadhesion properties.
2. The Science behind the Quality & Safety of Ellage
An important consideration for any base used in a vaginal compound is its effect on the mildly acidic vaginal pH (≈4.5). To verify whether Ellage affected pH, we prepared a VFS with a pH of 4.54 and placed it in a water bath at 98.6° F (37° C). We added Ellage to increasing volumes of the VFS and measured the pH of the resulting solutions in duplicate. The pH ranges we obtained (4.51–4.645) demonstrate that Ellage did not significantly change the baseline pH of the VFS.6
Another important consideration of a vaginal base is its potential to irritate tissue, so we tested Ellage to determine that it is nonirritating to the vaginal mucosa as well. We used the in vitro hen’s egg test – chorioallantoic membrane (HET-CAM) assay, which measures the ability to induce toxicity in the CAM of a chicken egg, to test the ocular/vaginal irritation potential of Ellage in comparison to positive and negative controls. Our test preliminary test demonstrated that Ellage has no ocular/vaginal irritation potential (irritation score <5), and it was confirmed by an outsourced study by the Consumer Product Testing Company in Fairfield, New Jersey.7
Additionally, we evaluated the safety and toxicological profile of Ellage using the MTT effective time 50 (ET50) in vitro assay, which consists of measuring the reduction of MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide) by the viable cells in the EpiVaginal™ tissue model. Following 24 hours of exposure to Ellage, the viability of the cells was 78%, as opposed to less than 3% after exposure to the spermicide Gynol II, which was the negative control. We obtained similar results for two reference OTC vaginal lubricants used as positive controls in this study.8
The Clinical Significance of the Quality & Safety
These findings show that Ellage should not affect vaginal pH, and it is expected to be nonirritating for vaginal tissue, which helps compounding pharmacists to ensure the quality and safety of their formulations that contain this base.
3. The Science behind the Efficacy of Ellage
As we developed this base, we knew that it must be effective at delivering APIs to vaginal tissue, so we evaluated its drug-release performance. We prepared a VFS and used it as the receptor medium in the Franz diffusion system to evaluate the in vitro drug release of amitriptyline 2% and baclofen 2% in Ellage versus VersaBase Cream as well as estriol 0.1% and testosterone 0.1% in Ellage versus VersaBase Cream. The results show that the amount of amitriptyline 2% and testosterone 0.1% released from VersaBase Cream was higher at all time points in the studies compared to Ellage. On the other hand, the amount of baclofen 2% and estriol 0.1% released from Ellage was higher at all time points in comparison to VersaBase Cream. These two comparative studies were not designed to evaluate any statistical differences between these two bases and are not intended to predict in vivo performance. However, they do show that Ellage has comparable in vitro performance to VersaBase Cream.9,10
The Clinical Significance of the Efficacy
These in vitro studies are important for compounding pharmacies to ensure comparable release profiles when drugs are incorporated in the newly developed Ellage versus the well-established VersaBase Cream.
For detailed information on the science behind Ellage Anhydrous Vaginal , please consult the corresponding technical reports at pccarx.com/science. PCCA members can also contact us at PCCAScience@pccarx.com.
Maria Carvalho, PharmD, MRPharmS, PhD, is the Manager of PCCA Science. She is a certified pharmacist in Portugal and the United Kingdom with a PhD in pharmaceutical compounding from the University College of London (UCL). Maria has worked in community pharmacy, hospital pharmacy and the pharmaceutical industry in Europe and the United States. She was a teaching assistant at the UCL School of Pharmacy (UK) and an invited teacher at the University Fernando Pessoa (Portugal). Maria has authored and co-authored many scientific publications, including the book Compounding Practices in Europe (ISBN-10:149236925X).
References
1. PCCA Science. (2020). Evaluation of the self-emulsifying properties of PCCA Ellage part 1: Microscopic evaluation [PCCA Document #99838]. http://beta.pccarx.com/pdf_files/PCCA%20Science/Technical%20Reports/99838_TR_Ellage-Self-EmulsProp-Part1.pdf
2. PCCA Science. (2020). Evaluation of the self-emulsifying properties of PCCA Ellage part 2: Fluorescence microscopy [PCCA Document #99839]. http://beta.pccarx.com/pdf_files/PCCA%20Science/Technical%20Reports/99839_TR_Ellage-Self-EmulsProp-Part2.pdf
3. PCCA Science. (2020). The leakage test: Evaluation of the leakage potential of PCCA Ellage [PCCA Document #99816]. http://www.pccarx.com/pdf_files/99816_TR_EllageLeakageTest.pdf
4. PCCA Science. (2020). Evaluation of the mucoadhesive properties of PCCA Ellage part 2: Ex vivo testing on animal vaginal tissues [PCCA Document #99837]. http://beta.pccarx.com/pdf_files/PCCA%20Science/Technical%20Reports/99837_TR_Ellage-MucoadhAnimalTissue-Part-2.pdf
5. PCCA Science. (2020). Evaluation of the mucoadhesive properties of PCCA Ellage part 1: Ex vivo bioadhesion testing using a texture analyzer [PCCA Document #99836]. http://beta.pccarx.com/pdf_files/PCCA%20Science/Technical%20Reports/99836_TR_Ellage-MucoadhTexture-Part-1.pdf
6. PCCA Science. (2020). Effect of Ellage and other PCCA proprietary bases on the pH of vaginal fluid [PCCA Document #99815]. http://www.pccarx.com/pdf_files/99815_TR_Ellage-VaginalpH.pdf
7. PCCA Science. (2020). Evaluation of the irritation potential of PCCA Ellage Anhydrous Vaginal part 1: Hen’s egg test-chorioallantoic membrane assay [PCCA Document #99817]. http://www.pccarx.com/pdf_files/99817_TR_Ellage-Irritation-Part-1.pdf
8. PCCA Science. (2020). Evaluation of the irritation potential of PCCA Ellage Anhydrous Vaginal part 2: Safety and toxicological profile by the MTT assay [PCCA Document #99818]. http://www.pccarx.com/pdf_files/99818_TR_Ellage-MucosalToxic-Part-2.pdf
9. PCCA Science. (2020). In vitro drug release of estriol 0.1% and testosterone 0.1% from VersaBase Cream and PCCA Ellage Anhydrous Vaginal [PCCA Document #99823]. http://beta.pccarx.com/pdf_files/PCCA%20Science/Technical%20Reports/99823_TR_Ellage-DrugRelease-E3-Test.pdf
10. PCCA Science. (2020). In vitro drug release of amitriptyline 2% and baclofen 2% from VersaBase Cream and PCCA Ellage Anhydrous Vaginal [PCCA Document #99824]. http://beta.pccarx.com/pdf_files/PCCA%20Science/Technical%20Reports/99824_TR_Ellage-DrugRelease-AmitrBaclof.pdf
These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.