To reduce the onus on the patient, several injectable and implantable long-acting contraceptives have been developed and approved for clinical use.
Center for Disease Control and Prevention provides information and guidelines on current birth control methods. Read more about these methods at: https://www.cdc.gov/reproductivehealth/contraception/index.htm
The dosage forms were retained in the stomach for the entirety of the experiment.
Both smart pills with long-acting formulation 1 and 2 were able to stay in the stomach for over 20 days and provided sustained drug release during this period, demonstrating their potential as once-a-month birth control pill.
To overcome the economic and cultural barriers in low-income countries, a long-acting contraceptive should have several key features. We believe that the orally administered long-acting contraceptive described here satisfies several of these considerations. These include (i) opportunity for self-administration, (ii) drug administration by the oral route, (iii) circumvention of the need for clinical procedures for dosage form removal, and (iv) maintenance of privacy. Hence, our technology stands to benefit a large patient population that prefers oral medication or is in regions of the world where self-medication is the only means to chronic therapy.
This long-acting smart birth control pill can help overcome cultural and economic barriers in low-income countries. This once-monthly smart pill would benefit a large patient population that cannot afford high-cost birth control methods such as implants.
Future successful human translation will require further development in dogs and humans with a focus on further optimal material selection for retention of the dosage form for the desired period and complete drug release in the prescribed period. Additional studies will be needed to test the contraceptive efficacy of this dosage form, which was not evaluated in these studies.
The authors concluded that they will need to do further testing in humans and animals to test different materials that will help keep the smart pill in the stomach for a desired period and release its drug content over this period. In addition, further testing is needed to verify the efficiency of this smart pill in preventing pregnancy.
Programmed exit of the dosage form from the stomach may be achieved by inclusion of tough materials that disintegrate in the presence of chemical or thermal stimuli (23, 28, 29) and pH-sensitive linkers to maximize safety in the setting of inadvertent transit across the pylorus (23, 25).
Here, the authors describe a possible improvement to their oral contraceptive. The authors suggest that by integrating chemically or thermally responsive materials, it might be possible to program the exit time of the smart pill. For instance, the arms can disintegrate after 21 days, allowing the dosage form to leave the stomach.
The first formulation (long-acting formulation–1) contained half the drug loaded into a PDMS matrix and the other half loaded into a poly(sebacic anhydride) matrix. The second formulation (long-acting formulation–2) had the entirety of the drug loaded into a PDMS matrix. Formulation-2 produced a peak concentration on day 2, after which concentrations slowly declined throughout the study. In contrast, formulation-1 produced comparable concentrations on days 3, 11, and 17, and changes in serum concentration were not unidirectional. Moreover, formulation-1 produced lower (undetectable at some time points) concentrations than formulation-2.
In the first formulation, the drug was loaded into two different polymer matrices (half into PDMS and half into polysebacic anhydride). In the second formulation, the entire drug was loaded in one polymer matrix (PDMS).
The first formulation resulted in continuous drug release over 20 days, however, the drug concentration in the serum was fluctuating quite a bit. In the second formulation, the drug concentration in the serum was initially high (similar to the tablet case), and steadily decreased over a 30-day period, however not as fast as the tablet form.
To enable protection of drug from the gastric environment and sustained release, we encapsulated the drug in polymer matrices.
The authors used a polymer to coat the device so that the gastric environment doesn't degrade the drug too quickly and makes sure the drug releases evenly and consistently. This explains how authors developed a solution for the second problem listed above.
To address the issue of gastric residence, we chose materials and geometries that were highly durable and evaluated their performance using a series of mechanical tests.
The movements of the stomach can break the arms of the smart pill, causing its early unintended exit. To prevent this, authors chose geometries and materials and tested their mechanical properties to make sure that the smart pill would resist the harsh acidic environment in the stomach.
We detected drug in serum up to 29 days after administration of long-acting formulation–2, when the average serum concentration was 13 ± 2 pg/ml (n = 3).
Using long-acting formulation 2, the authors detected drug in the serum for 29 days where the serum concentration remained above 10pg/ml. long-lasting formulation 1 resulted in drug concentrations which fluctuated over the 30-day period whereas long-lasting formulation 2 lead to steady decrease in drug concentration over the same period.
Twenty-four hours after dosing, the average concentration fell to 16% of the maximum concentration (32 ± 6 pg/ml, n = 5), and by 48 hours, the average concentration was reduced to 5 ± 4 pg/ml (n = 5).
After 24 hours, the average drug concentration dropped to 16% of the maximum concentration. After 48 hours, it dropped to 2.5% of the maximum concentration. Therefore, the Levora tablets provide pregnancy protection for only a day.
This dosage form fits in a 000 capsule to enable oral administration and recoils in the stomach to assume a size larger than the pylorus. This latter property enables the dosage form to reside in the stomach, where it releases levonorgestrel.
Smart pill is introduced as a capsule so that it is easy for the patient to swallow and get to the stomach. In the stomach, the capsule dissolves allowing the 6 arms to unfold such that the device is large enough to stay in the stomach for a month and release the drug over time.
We then synthesized poly(sebacic anhydride) and PDMS matrices loaded with increasing amounts of levonorgestrel and analyzed drug release in vitro (Fig. 1, F and G). Drug release occurred at a near-constant rate from both matrices, and it was affected by the type of polymer matrix and amount of drug loaded.
The authors tested the release of the contraceptive drug (levonorgestrel) loaded within a biodegradable polymer matrix (polysebacic anhydride) and another biocompatible polymer matrix (PDMS) at different concentrations (12.5, 25, 40, 50%). The authors monitored the percentage of drug released over 30 days while in the simulated gastric fluid. Drug release occurred at a near constant rate. The lower the drug concentration the faster the drug release. Drug release from PDMS matrices was slower than that from polysebacic anhydride matrices. The author concluded that by changing the matrix, the rate of drug release could be altered.
Because of the higher surface area afforded by the slotted holes, we pursued this design further.
The caged slotted holes were better than the v-shaped and caged circular holes. It allowed for optimal, sustained release of the drug over a month. This geometry provided enough surface area for effective release of the drug, while also limiting the exposure so the medicine did not run out before the month was over.
Despite this, the arms retained sufficient rigidity appropriate for incorporation in the dosage forms.
Even with a decrease in flexural strength, the arms of the smart pill still have sufficient rigidity to move forward with the experiment. If the rigidity was affected more drastically, it could lead to the arms breaking inside the stomach. The arms are meant to keep the smart pill large enough so that it is too big to pass through the pylorus, therefore arm breakage could lead to early digestion of the pill.
folding into a capsule to facilitate oral administration
The smart pill is able to fold into itself to fit inside a capsule for ingestion.
2 of the 18 arms detached from the dosage form body within 30 days after ingestion. It is likely that the amount of drug delivered and gastric retention would be adversely affected if more arms were lost or if arms were lost early. Loss of arms at later times during the dosing period, when most of the drug is released, will not affect the efficacy of the system.
Since the arms contain the drug, losing arms would reduce the total amount of drug to be released. In addition, if arms are lost, the dosage form can pass through pylorus, and move into small intestine, and the birth control drug will no longer be effective. Therefore, the stability of the arms ensure that the smart pill is retained in the stomach and provides sustained drug release over extended periods.
Using this dosage form, we have shown 1- to 2-week-long delivery of anti-infectious disease agents previously (23, 25); however, month-long delivery of contraceptives has yet to be achieved.
The authors have previously shown that this smart pill can release drug for infectious diseases for a period of 1-2 weeks. Here, the authors extend this time to 4 weeks for the oral contraceptive application.
levonorgestrel-releasing gastric resident dosage form
A smart pill that stays in the stomach during release of a drug (levonorgestrel) which prevents pregnancy.
We analyzed the stability of levonorgestrel in SGF for 24 hours and observed no significant degradation (96.3 ± 4.3 μg/ml, n = 5 versus 90.4 ± 9.6 μg/ml, n = 5; P = 0.122, Student’s t test) (Fig. 1E).
The authors tested the stability of the birth control drug (levonorgestrel) in a highly acidic environment (simulated gastric fluid) at body temperature over 24 hours mimicking the conditions in the stomach. The authors did not observe any significant degradation. The drug concentration stayed around 90 μg/mL over the 24 hours. This essentially shows that the smart pill residing in the stomach can successfully deliver the birth control drug over an extended period.
The flexural strength of the arms was reduced after 2 weeks of incubation in SGF
After a period of 2 weeks in the simulated stomach acid, the strength of the caged arms decreased. The integrity of the polymeric arms are affected by exposure to the acid. The decrease in strength is ~25% after 2 weeks.
poly(dimethylsiloxane)
A silicon based elastomeric polymer used in biomedical applications.
assumes a size larger than that of the pylorus;
After ingestion, the smart pill is released from the capsule and expands to a size larger than the stomach's opening, which prevents it from passing into small intestine. This will allow for the extended release of the birth control drug within the stomach.
To address this issue, we have developed a gastric resident dosage form that can be placed in a gelatin capsule to enable oral administration.
The author's created a pill that can be swallowed and could stay in the digestive tract for about a month. The drug is slowly administered over the month instead of being absorbed right away.
hormonal contraception
methods of birth control which impacts hormones related to pregnancy
in vivo
in live being
Solid arms made of Sorona 3015G NC010 were placed in simulated gastric fluid (SGF) for various times
The simulated gastric fluid is a manmade fluid to mimic the acidic condition in human stomach. This fluid is used for testing the stability of the polymer that the solid arms are made of, for prolonged periods.
we decided to use PDMS-based polymer matrices
PDMS-based material was used in this experiment because there are known uses for this material in other sustained- release products.
oral contraceptives
A drug or device used to prevent pregnancy taken as a pill by mouth.
vaginal rings,
A flexible transparent ring of plastic placed in the vagina and releases estrogen and progestogen. This needs to be replaced once a month.
Hence, an orally administered long-acting contraceptive could improve patient adherence in the population that prefers pills.
Constructing Explanations and Designing Solutions (SEP6): Evaluate a solution to a complex real world problem, based on scientific knowledge, student generated sources of evidence, prioritized criteria, and trade off considerations.
Further pharmacokinetic-pharmacodynamic studies (experiments and/or simulations) evaluating efficacy and safety may aid in identifying lead formulations for clinical translation.
The Common Core English and Language Arts Standards: RST.11-12.4: Determine the meaning symbols, key terms, and other domain specific words and phrases as they are used in a specific scientific or technical context relevant to grades 11-12 texts and topics.
These interventions enable spacing of pregnancies, which can help support the health of both the infant and the mother.
National Health Education Standards SM-7: students will demonstrate the ability to practice health-enhancing behaviors and avoid or reduce health risks.
levonorgestrel
A synthetic steroid hormone that has similar effects on the body to progesterone and is often used in contraceptive pills.
elastomeric
An elastic substance occurring naturally or synthetically.
poly(caprolactone)
A polymer often used to improve a products processing characteristics, and its compatibility with other materials. It can be used to increase biodegradability, or used with a polymeric to plasticize a product.
poly(lactide-co-glycolide)
A copolymer which is widely accepted for biomedical applications due to its biocompatibility, biodegradation rate, approval for clinical use, potential modification properties, and export opportunities to cultures with unpopular use of animal- derived products.