markedly lower than those observed in humans (27)
Kook and colleagues studied the plasma levonorgestrel concentrations following the oral administration of Levora tablets in females between the ages of 19 and 44. The mean concentration observed was 14.1 +/- 7.9 ng/mL.
This data serves as a comparison for the serum concentrations that was observed in the pigs.
While the drug concentration in the serum is in the range of nanograms/ml in humans, it is in the picograms/ml range in pigs.
reported to be ~1.7 to 1.9 cm (26).
Dr. Salessiotis experimentally measured the diameter of a fully functioning pylorus. It was concluded that a diameter of 1.9 cm was never exceeded.
When unfolded, the smart pill spans larger than this reported size.
Daily oral pills are favored by a sizeable fraction of the population (16–19), possibly because of their ease of use, opportunity for self-administration, and rapid resumption of fertility upon discontinuation.
Read more about some of the advantages of using an oral pill over other birth control methods at: https://www.verywellhealth.com/the-pill-pros-vs-cons-906927
J. Liu, Y. Pang, S. Zhang, C. Cleveland, X. Yin, L. Booth, J. Lin, Y.-A. L. Lee, H. Mazdiyasni, S. Saxton, A. R. Kirtane, T. von Erlach, J. Rogner, R. Langer, G. Traverso, Triggerable tough hydrogels for gastric resident dosage forms. Nat. Commun. 8, 124 (2017).
Liu and colleagues created "triggerable tough hydrogels," composed of novel materials that promote a prolonged stay in the gastric system.
The once-monthly smart birth control pill employs this concept of tough materials that will only disintegrate in the presence of chemical stimuli to ensure the contraceptive will stay in the digestive tract longer.
A. M. Bellinger, M. Jafari, T. M. Grant, S. Zhang, H. C. Slater, E. A. Wenger, S. Mo, Y.-A. L. Lee, H. Mazdiyasni, L. Kogan, R. Barman, C. Cleveland, L. Booth, T. Bensel, D. Minahan, H. M. Hurowitz, T. Tai, J. Daily, B. Nikolic, L. Wood, P. A. Eckhoff, R. Langer, G. Traverso, Oral, ultra–long-lasting drug delivery: Application toward malaria elimination goals. Sci. Transl. Med. 8, 365ra157 (2016).
Bellinger and colleagues design a long-term drug delivery system for malaria. They accomplish this by designing an oral capsule that stays in the gastric cavity for up to 14 days.
The smart birth control pill presented in this work builds off of this research and the idea that reducing dosage frequency can be accomplished by increasing the time it stays in the stomach.
A. Hayward, T. Bensel, H. Mazdiyasni, J. Rogner, A. R. Kirtane, Y.-A. L. Lee, T. Hua, A. Bajpayee, J. Collins, S. McDonnell, C. Cleveland, A. Lopes, A. Wahane, R. Langer, G. Traverso, Scalable gastric resident systems for veterinary application. Sci. Rep. 8, 11816 (2018).
A study was performed to investigate scalable doses and the modulation of drug release in the gastrointestinal system.
The author's used most of the characteristics of these dosage forms in the manufacturing of the oral contraceptive.
Passage of the dosage form from the body was not studied here; although pigs are recognized as having gastric anatomy comparable in dimension to humans, transit times are recognized to be slower (25, 30). Intestinal passage time will not be important to serum drug levels if the dosage form has released all of its contents.
The passage times of ingested food/drugs through the digestive system is slower in pigs compared to humans. Therefore, before applied to humans, the design of the smart pill should be modified. The smart pill's residence time in the stomach should be lengthened and the period of drug release should be shortened. This design change will ensure that the smart pill releases all its drug content while in the digestive system.
previously applied in weekly oral formulation systems (23).
Kirtane and colleagues developed a once-weekly oral drug delivery system for HIV medication. The smart pill was unique in its drug-polymer matrices, which allowed week-long drug delivery at the desired concentration.
This matrix-based system was applied to the smart pill developed in this work.
30. V. Snoeck, N. Huyghebaert, E. Cox, A. Vermeire, J. Saunders, J. P. Remon, F. Verschooten, B. M. Goddeeris, Gastrointestinal transit time of nondisintegrating radio-opaque pellets in suckling and recently weaned piglets. J. Control. Release 94, 143–153 (2004).
Snoeck and colleagues determine the time it takes for a dosage form to pass through pigs. This information can help in the design of oral drug delivery methods.
12. United States Food and Drug Administration, Nuva Ring FDA label, (2013); www.accessdata.fda.gov/drugsatfda_docs/label/2013/021187s022lbl.pdf. 13. United States Food and Drug Administration, Ortho Evra FDA label, (2014); www.accessdata.fda.gov/drugsatfda_docs/label/2014/021180Orig1s046lbl.pdf.
The authors discuss the current alternative contraceptive forms that provide shorter-term protection (about 1 month).
3. R. H. Allen, C. A. Cwiak, A. M. Kaunitz, Contraception in women over 40 years of age. Can. Med. Assoc. J. 185, 565–573 (2013).
Allen and colleagues discuss the use of contraceptives as a form of family planning in women over the age of 40. Due to being at the end of the reproductive age range, special attributes of the effects of contraceptives for women over 40 need to be considered.
5. United States Food and Drug Administration, Nexplanon FDA label, (2015); www.accessdata.fda.gov/drugsatfda_docs/label/2015/021529s011lbl.pdf. 6. United States Food and Drug Administration, Implanon information leaflet, (2008); www.accessdata.fda.gov/drugsatfda_docs/label/2009/021529s004lbl.pdf.
The authors discuss that some contraceptive devices can be implanted outside of the uterus and release hormones for about 3 years, after which they are surgically removed.
1. World Health Organization, “Family planning/contraception,” (2018); www.who.int/ news-room/fact-sheets/detail/family-planning-contraception.
The World Health Organization describes the vast impacts of contraceptives, ranging from its role in family planning to its involvement in protecting from sexually transmitted infections, as well as the many different forms of contraceptives that are available.
Hence, the impact of female contraceptives on global good cannot be underestimated.
Read more about the efforts that are needed to meet international family planning goals at: https://www.who.int/reproductivehealth/topics/family_planning/contraceptive-access-women-and-girls/en/
microneedles are also being developed as a pain-free means of administering long-term contraceptives
The use of microneedles has been proposed as an alternative contraceptive, which works through applying a pain-free patch that administers hormones at regulated times.
In situ–forming drug depots that are made by injecting drug, polymer, and a safe organic solvent have also been described
Wu and colleagues reviewed past strategies of developing injectable hormonal contraceptives. Their analysis describes the use of injections to form drug deposits as a long-term contraceptive option.
40 to 50% of women missed at least one dose. A similar percentage of women reported to have taken the medication at the wrong time (19).
Hooper studied contraceptive pill users by analyzing the results of an online questionnaire. The attitudes, awareness, compliance, and preferences of users were assessed.
Analysis revealed non-compliance (failing to take a pill altogether or taking a pill at the wrong time) by many users, including missed doses or doses taken at an incorrect time.
expands and resides in the stomach
A similar oral capsule design has been introduced for a once-weekly HIV medication.
Read more about how expandable pills are being implemented into other medication regimens: https://scitechdaily.com/new-drug-capsule-delivers-a-weeks-worth-of-hiv-drugs-in-a-single-dose/
Pharmacokinetics
Pharmacokinetics plays a significant role in the development of drugs. Read more about how scientists are getting closer to tracking compounds at the cellular level: https://blogs.sciencemag.org/pipeline/archives/2018/06/20/looking-way-down-into-the-cells
4. Centers Disease Control and Prevention, “Contraception,” (2018); www.cdc.gov/reproductivehealth/contraception/index.htm.
The Center for Disease Control and Prevention describes existing methods of contraception. In addition to oral pills, other methods include subcutaneous implants, intrauterine devices, vaginal rings, transdermal patches, and injectables.
Patient adherence to medications can be increased by reducing dosing frequency (21).
Iglay, Cao, Mavros, Joshi, Yu, and Tunceli reviewed twenty-two observational studies regarding how often chronic disease patients took their medication. Patients prescribed once-weekly and once-daily doses were compared.
The analysis showed that patients needing to take doses once a week were more likely to take their medication than patients needing to take doses once a day.
R. Hatcher, Contraceptive Technology, D. Kowal, R. A. Hatcher, A. L. Nelson, J. Trussell, C. Cwiak, P. Cason, M. S. Policar, A. B. Edelman, A. R. A. Aiken, J. M. Marrazzo, Eds. (Managing Contraception LLC, ed. 21, 2018)
Statistics show that "the chance of pregnancy in women using oral contraceptive pills is ~9% per year," signifying the need for improving oral contraceptives.
7. United States Food Drug and Administration, Mirena FDA label, (2015); www.accessdata.fda.gov/drugsatfda_docs/label/2015/021225s031lbl.pdf). 8. United States Food Drug and Administration, Liletta FDA label, (2018); www.accessdata.fda.gov/drugsatfda_docs/label/2018/206229s007lbl.pdf). 9. United States Food and Drug Administration, Kyleena FDA label, (2016); www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208224Orig1s000LBL.pdf. 10. United States Food and Drug Administration, Skyla FDA label, (2017); www.accessdata.fda.gov/drugsatfda_docs/label/2017/203159s007lbl.pdf.
The authors discuss that intrauterine (within the uterus) hormone devices can serve as an alternative contraceptive form, providing protection for 3-6 years.
Adherence to monthly therapies is greater than adherence to weekly and daily therapies (22).
Kishimoto and Maehara studied and compared adherence to daily, weekly, and monthly doses of medication for osteoporosis patients.
The study revealed that monthly medication regimens had better patient adherence than weekly and daily medication regimens.