"Transdermal Drug Delivery Application in Psychiatry" by Zohra Ahmed

Transdermal Drug Delivery Application in Psychiatry

Zohra Ahmed, Notre Dame of Maryland University




Abstract: The overall message to be emphasized is the need for innovation and enhanced variety in psychiatry, which can in return increase the effectiveness of the treatments that are provided within the field. There are many psychological disorders that have a poor prognosis and poorer treatment responses (Parmar & Kaloiya, 2018). Ineffectiveness may be brought on by severe side effects of medications, interactions with other medications and substances, consequences of long-term use, and forgetfulness. The need for effective treatments is crucial, as psychological disorders tend to be severe and debilitating. Introducing the usage of transdermal patches as an alternative to daily assorted pills may be a step toward revolutionizing the treatment of psychological disorders. The objectives of this study were to investigate the components of transdermal patches, explore psychiatric classifications and drugs, discuss the chemical elements that allow drugs to function in transdermal modes, pinpoint some [psychiatric] drugs that may be used in transdermal modes, and examine ways to bypass insufficient properties. The hypothesis which has been accepted states that transdermal patches may be introduced for the treatment of certain psychological disorders, serving as an alternative to the pill form of psychiatric medications.


Keywords: psychiatric medication, transdermal patches, drug delivery systems



Introduction


The types of medication administered may overlap when treating various psychological disorders. Generally, the types of medication in psychiatry include five classes: stimulants, antidepressants, antipsychotics, mood stabilizers, and antianxiety agents (Rao & Andrade, 2016). There are several modes of administering medication, including oral methods, injections, liquid formulations, and transdermal systems. Certain psychological disorders have been treated with more than one mode of medication administration, due to varying effects. Attention-Deficit Hyperactivity Disorder (ADHD) has been treated through oral medications, including stimulant and non-stimulant pills, injections, liquid extended-release products (Quillivant XR), and transdermal patches, specifically the methylphenidate patch (Findling & Dinh, 2014). Transdermal modes, in particular, are relatively newer and have surfaced an array of benefits.




Transdermal patches represent growth in the evolution of drug delivery (Pastore et al., 2015). Currently, transdermal patches are being studied and utilized for the treatment of many illnesses.


Transdermal patches utilize a topical mode to deliver drugs, in which the molecules may be absorbed by the skin into the bloodstream, for a specific amount of time (Isaac & Holvey, 2012). There are many advantages of transdermal drug delivery. Isaac & Holvey (2012) discussed the advantages of easy use, tolerability, use of lower doses to obtain the same desired outcome, reduced frequency of dosing, constant drug serum level, reduced side effects, simple administration by a parent or guardian, easier titration, reduction of the risk of a drug overdose, and the fact that removal of the patch stops drug delivery. Skin is complex, encompassing a changing environment in layers that influence the route of molecules that attempt to enter through, allowing components or characteristics that are favorable to be determined. Studying the components of transdermal patches is important to understand how they may function as a mode of psychiatric drug delivery. The drug components relevant to transdermal modes of administration that were assessed in this study include molecular weight, qualitative solubility, lipophilicity, and relative potency. Two external studies, Leeson & Young (2015) as well as Gupta et al. (2018), aided with the formulation of definitions for the components relevant to transdermal modes. Leeson & Young (2015) discussed molecular property design, defining and describing molecular components and property optimization trajectories in drug design, while Gupta et al. (2018) examined physicochemical and biological properties of active pharmaceutical ingredients (APIs) and ways molecules may achieve desirable formulation properties. Molecular weight is a component that pertains to the sum of all atomic masses of the atoms in a molecule, observed in the unit grams per mole. Solubility is the ability to be dissolved, investigated qualitatively in this study. Lipophilicity pertains to solubility in lipids or oils measured by log P (partition coefficient), which is the ratio of solubility of a drug in two solvents, often oil and water. Relative potency refers to the strength of a compound in terms of the concentration or amount that is necessary to produce a desired effect; a lower dose with more effect indicates a higher potency. This study explored the components of molecular weight, qualitative solubility, lipophilicity, and relative potency in five drugs that are currently used in transdermal modes, as well as fourteen drugs among the categories of drugs classified as antipsychotics, anti-anxiety, and antidepressants which are not currently used in transdermal modes.


Method


Current drugs used in transdermal modes were identified and investigated. Estrogen, Duragesic, Xylocaine, Daytrana, and nicotine are five substances that are currently used in transdermal drug delivery systems. PubChem and FDA-approved drug databases were searched to compile data for each of the drugs relevant to transdermal systems, including molecular weight, qualitative solubility, lipophilicity, and relative potency. General trends were noted for current transdermal drug delivery systems using the data gathered. Upon investigating the classifications and categories of psychiatric medications, the categories of antipsychotics, anti-anxiety agents, and antidepressants were highlighted due to notorious side effects, general issues, and varying effectiveness. Utilizing the same databases mentioned previously and literature about the drugs within each category, specific substances were noted to further investigate in this project. The names of each of the substances, as well as their active pharmaceutical ingredient (API), were gathered. The antipsychotics that were explored include Abilify, Zyprexa, Clozaril, Seroquel, and Risperdal. The anti-anxiety agents that were explored include Klonopin, Ativan, Valium Vistaril, and Buspar. The antidepressants that were explored were Zoloft, Prozac, Paxil, and Lexapro. The same data that was gathered for the proposed molecules was gathered for five drugs that are currently used in transdermal modes, estrogen, Duragesic, Xylocaine, Daytrana, and nicotine. The chemical structures of each of the molecules investigated in this study were constructed using chemical drawing software. Based on current transdermal drug delivery system trends, the proposed drugs were assessed to observe which molecules had components within the range of current successful modes. The drugs to consider using in transdermal systems were pinpointed. Methods to bypass insufficient properties were explored to derive solutions and further discussion.


Results


The data that was gathered in the study was compiled into tables. Generally, an ideal drug molecule, or API, has characteristics that allow optimal function in transdermal systems. Based on table 1, the molecular weight of drugs currently used in transdermal modes ranges from 162.23 to 336.47 g/mol, favoring a low molecular weight. Another trend that may be observed with current drugs used in transdermal systems is that solubility varies with an emphasis on increased ability to dissolve in organic solvents. The log P of drugs currently used in transdermal modes ranges from 1.17 to 3.9 (see table 1). Moderate lipophilicity is advantageous as the API must move through the increasing hydrophilic environment of live cells contained in the lower epidermis to reach blood vessels. The final trend that may be observed is a high relative potency, instrumental to allowing drugs to circulate through the bloodstream and have an effect even if there is very little active ingredient present. Figure 1 depicts the chemical structures of drugs from the first table. Figures 2, 3, and 4 depict the chemical structures of the drugs from the three categories of psychiatric medications of antipsychotics (see fig. 2), anti-anxiety agents (see fig. 3), and antidepressants (see fig. 4), including a comparison of drug components to current systems, stating whether a molecule fits the conditions or has components that do not fit the conditions of drugs currently used in transdermal systems. The drugs that may be considered in transdermal systems include Zyprexa, Clozaril, Klonopin, Ativan, Valium, and Lexapro.




Table 1: Drug Components of Substances Used Currently in Transdermal Modes

Note. PubChem and FDA Approved Drug databases were used to compile this data. The category, name, active pharmaceutical ingredient (API), molecular weight (g/mol), general qualitative solubility, lipophilicity as a log P- ratio, and potency were recorded for each drug. The potency of drugs was classified qualitatively, either low, medium, or high depending on starting doses. All of the drugs listed in this table are currently used and have been observed as effective in the transdermal mode of administration.




Table 2: Drug Components of Proposed Substances to be Used in Transdermal Systems

Note. PubChem and FDA Approved Drug databases were used to compile this data. The category, name, active pharmaceutical ingredient (API), molecular weight (g/mol), general qualitative solubility, lipophilicity as a log P- ratio, and potency were recorded for each drug. The Log P of a salt may not be calculated, so it is distinguished by a negative label. The potency of drugs was classified qualitatively, either low, medium, or high depending on starting doses. These drugs are not currently administered in transdermal modes.



Figure 1: Chemical Structures of Drugs Currently Used in Transdermal Systems

Note. Chemical drawing software was used to construct the chemical structures. The five drugs used in current transdermal drug systems that were explored in this study include estrogen, Duragesic, Xylocaine, Daytrana, and nicotine.





Figure 2: Chemical Structures of Antipsychotics

Note. Chemical drawing software was used to construct the chemical structures. Five antipsychotics were investigated in this study, Abilify, Zyprexa, Clozaril, Seroquel, and Risperdal. The components of drug delivery (i.e. molecular weight, solubility, lipophilicity, and relative potency) were compared to current systems. Zyprexa and Clozaril appear to meet the conditions for transdermal drug delivery. Abilify, Seroquel, and Risperdal exceed the molecular weight range, and Abilify also exceeds the log P range. Larger and more complex molecules have a more difficult time crossing the phospholipid bilayer in comparison to smaller molecules with smaller molecular weights.




Figure 3: Chemical Structures of Anti-Anxiety Agents

Note. Chemical drawing software was used to construct the chemical structures. The five antianxiety agents explored in the study include Klonopin, Ativan, Valium, Vistaril, and Buspar. The components of drug delivery (i.e. molecular weight, solubility, lipophilicity, and relative potency) were compared to current systems. Klonopin, Ativan, and Valium appear to meet the conditions for transdermal drug delivery. Vistaril and Buspar exceed the log P range. HCl is a strong acid and a salt, contained in the two molecules that do not meet the conditions. These molecules are water-soluble and hydrophilic, making their most ideal mode of administration oral.



Figure 4: Chemical Structures of Antidepressants

Note. Chemical drawing software was used to construct the chemical structures. The four antidepressants that were examined in the study include Zoloft, Prozac, Paxil, and Lexapro. The components of drug delivery (i.e. molecular weight, solubility, lipophilicity, and relative potency) were compared to current systems. Lexapro appears to meet the conditions for transdermal drug delivery. Zoloft, Prozac, and Paxil exceed the log P range. HCl is a strong acid and a salt, contained in the three molecules that do not meet the conditions. These molecules are water-soluble and hydrophilic, making their most ideal mode of administration oral.


Discussion


There are components of transdermal drug delivery that may be used to assess the ability of molecules to function in the form of a transdermal patch. The components discussed in this study include molecular weight, qualitative solubility, lipophilicity, and relative potency. The drugs that may be considered in transdermal systems, Zyprexa, Clozaril, Klonopin, Ativan, Valium, and Lexapro, met similar conditions of those molecules that are currently used in transdermal drug delivery systems. The other drugs that were investigated in this study did not meet the conditions of those drugs that are currently used in transdermal systems, however, there are methods that may enhance transdermal delivery, allowing molecules to bypass insufficient or exceeding properties. Some of the ways drugs may be enhanced to be used in transdermal systems are through heat assistance, utilizing temperature, iontophoresis, involving electrical currents, and microneedles, providing injection-based support.

Heat assistance is relevant to solubility, an important thermodynamic element relevant to establishing diffusion pathways. Temperature and solubility are positively correlated with one another, as an increase in temperature yields an increase in solubility. The heat generated from a heated transdermal patch system may lead to effective exertion of drug and functional permeability (Otto & de Villiers, 2014). There are two methods that heat assistance may be utilized in transdermal drug systems. The first method of heat assistance is a transdermal patch that contains a heating system or sources, such as iron powder which is activated after adhesion of patch to the target area on the skin, which may be the arm, abdomen, back, or torso (Otto & de Villiers, 2014). There are permeation differences at different places on the body, so the location at which a patch is being administered may be chosen selectively. Another method of heating assistance incorporates remote-controlled microheaters to control heat manually or through the presence of nanoparticles (Otto & de Villiers, 2014). Figure 5 depicts two methods of heat assistance. Heat assistance may be an effective way of enhancing drug solubility and the process of perfusion. There are other technologies that are relevant to drug permeation.


Iontophoresis is another method of enhancing the molecular properties of a drug to enable transdermal administration. The process of iontophoresis utilizes an electric current to drive a drug through the skin (see figure 6). Through advanced technology, iontophoresis promotes localized, superficial permeation of a therapeutic agent through the skin in the context of transdermal drug delivery (Sheikh & Dua, 2020). Iontophoresis may provide several benefits. There is a controlled and predictable release of drugs into the bloodstream of patients, greater permeability and uptake by skin, effective delivery of substances with large molecular weights and charged compounds, and an increased concentration of the drug may be administered in a target area (Yang et al., 2017; Bai et al., 2014). Iontophoresis has been applied in many settings. The most common use of transdermal iontophoresis has been found in the delivery of anti-inflammatory agents for the treatment of physical illnesses, such as arthritis and tendonitis, but has also been implemented in the systemic delivery of drugs, such as fentanyl for analgesia, antimigraine agents for headaches, tacrine III for Alzheimer’s, and more (Sheikh & Dua, 2020). There is a possibility that iontophoresis may be used in transdermal drug delivery systems involving substances that have a greater molecular weight and varying solubility.


Microneedles are a third method for enhancing transdermal administration. Microneedle patches incorporate micro-sized, self-dissolvable needles to bypass the outermost layer of the skin, stratum corneum, and transmit a particular substance through the circulatory system (Waghule et al., 2018). The microneedles contained within a transdermal patch penetrate the skin enough to supply a particular substance (see figure 7). There are multiple capacities that microneedles may fulfill in the context of transdermal delivery systems. Halder et al. (2020) discussed the ability of microneedle patches to deliver large molecules with higher masses, which includes insulin or vaccines, as well as water-soluble molecules. Microneedles have been regarded as an ideal enhancement to transdermal systems. Micron-scale pathways increase skin permeability and hollow microneedles have the potential to entertain connective flow and transport fluid or encapsulated cargo across the membrane (Prausnitz & Langer, 2008). Microneedle patches may be used for some of the medications that have greater molecular weight, such as antipsychotics. Seroquel is one of the antipsychotics that was investigated in the study, having a molecular weight that exceeded the range for optimal transdermal function. Seroquel is most commonly used orally, however, it has also been applied in the form of an injection as well as a liquid (Papazisis & Siafis, 2019). Evidently, microneedle patches may be another method of transporting drugs across biological barriers.


The mechanisms of heat assistance, iontophoresis, and microneedles may be used to effectively administer drugs through transdermal modes if they do not naturally meet the conditions for optimal transdermal drug delivery. Exploring alternative methods of administration is crucial, as current medications or administration methods may not be effective for all individuals being treated for psychiatric conditions. Psychological disorders are debilitating, and every individual has a unique experience with medications. Finding effective treatments and improving the rate of treatment responses may seem like a difficult or impossible feat, though hope is proximal, and transdermal drug delivery systems may be an essential element to progressing in the field of psychiatry. The future may hold the creation of a deliverable transdermal patch incorporating the drugs that were investigated in this study. Transdermal patches may be introduced as an alternative to current psychiatric medications.



Figure 5: Heat Assistance in Transdermal Systems

Note. Two methods of heat assistance in transdermal systems. Method 1 depicts an embedded heating system that is activated upon adhesion of patch to the skin, releasing the molecules stored in the drug reservoir. Method 2 depicts a remote-controlled microheater used to control heat manually to facilitate transdermal administration of a drug. Method 2 depicts a relatively small microheater, however, it is possible that microheater systems may be larger than the transdermal system itself that is hooked on the skin. Method 1 involves fewer moving pieces, serving as the more cost-efficient option.



Figure 6: Active Iontophoresis

Note. An illustration of active iontophoresis propelling a particular cationic drug through the skin by an active electrode, or anode. The electric current used in iontophoresis is physiologically tolerable. This figure depicts the pathway of a charged drug into the skin. The flow of ions is achievable due to the current, allowing the drug to travel below the surface of the skin to the target area.





Figure 7: The Use of Microneedles in Transdermal Systems

Note. An illustration of a transdermal drug delivery method that utilizes microneedles. The needles penetrate through the skin. The size and amount of microneedles in this graphic were altered for simplicity.


References


Bai, Y., Sachdeva, V., Kim, H., Friden, P.M., & Banga, A.K. (2014). Transdermal delivery of

proteins using a combination of iontophoresis and microporation. Therapeutic delivery, 5(5). https://doi.org/10.4155/tde.14.19


Findling, R. L., & Dinh, S. (2014). Transdermal therapy for attention-deficit hyperactivity

disorder with the methylphenidate patch (MTS). CNS drugs, 28(3), 217–228. https://doi.org/10.1007/s40263-014-0141-y


Gupta, D., Bhatia, D., Dave, V., Sutariya, V., & Varghese Gupta, S. (2018). Salts of therapeutic

agents: Chemical, physicochemical, and biological considerations. Molecules (Basel, Switzerland), 23(7), 1719. https://doi.org/10.3390/molecules23071719


Halder, J., Gupta, S., Kumari, R., Gupta, G. D., & Rai, V. K. (2020). Microneedle Array:

Applications, recent advances, and clinical pertinence in transdermal drug delivery. Journal of pharmaceutical innovation, 1–8. https://doi.org/10.1007/s12247-020-09460-2


Isaac, M., & Holvey, C. (2012). Transdermal patches: the emerging mode of drug delivery

system in psychiatry. Therapeutic advances in psychopharmacology, 2(6), 255–263. https://doi.org/10.1177/2045125312458311


Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2019). PubChem in 202: new data content and improved web interfaces. Nucleic acids research, 49(D1), D1388–D1395. https://doi.org/10.1093/nar/gkaa971


Leeson, P. D., & Young, R. J. (2015). Molecular property design: Does everyone get it? ACS

medicinal chemistry letters, 6(7), 722–725. https://doi.org/10.1021/acsmedchemlett.5b00157


Otto, D.P., & de Villiers, M.M. (2014). What is the future of heated transdermal delivery

Systems? Therapeutic delivery, 5(9), 961-964. https://doi.org/10.4155/tde.14.66


Parmar, A., & Kaloiya, G. (2018). Comorbidity of personality disorder among substance use

disorder patients: A narrative review. Indian journal of psychological medicine, 40(6), 517–527. https://doi.org/10.4103/IJPSYM.IJPSYM_164_18


Pastore, M. N., Kalia, Y. N., Horstmann, M., & Roberts, M. S. (2015). Transdermal patches:

history, development and pharmacology. British journal of pharmacology, 172(9), 2179–2209. https://doi.org/10.1111/bph.13059


Papazisis, G., & Siafis, S. (2019). The Added Value of Liquid Antipsychotics: The Case of

Quetiapine. Current clinical pharmacology, 14(2), 101–107. https://doi.org/10.2174/1574884713666181102145236


Prausnitz, M. R., & Langer, R. (2008). Transdermal drug delivery. Nature biotechnology, 26(11), 1261–1268. https://doi.org/10.1038/nbt.1504


Rao, T. S., & Andrade, C. (2016). Classification of psychotropic drugs:

Problems, solutions, and more problems. Indian journal of psychiatry, 58(2), 111–113. https://doi.org/10.4103/0019-5545.183771


Sheikh, N.K., & Dua, A. (2020). Iontophoresis analgesic medications. StatPearls Publishing.

Available from: https://www.ncbi.nlm.nih.gov/books/NBK553090/


Waghule, T., Singhvi, G., Dubey, S.K., Pandey, M.M., Gupta, G., Singh, M., & Dua, K. (2018).

Microneedles: A smart approach and increasing potential for transdermal drug delivery system. Biomedicine and pharmacotherapy, 109, 1249-1258. https://doi.org/10.1016/j.biopha.2018.10.078


U.S. Food and Drug Administration. (2021). FDA-Approved Drugs. Available from:

https://www.accessdata.fda.gov/scripts/cder/daf/


Yang, R., Wei, T., Goldberg, H., Wang, W., Cullion, K., & Kohane, D. S. (2017). Getting drugs

across biological barriers. Advanced materials, 29(37), 10.1002/adma.201606596. https://doi.org/10.1002/adma.201606596