Drug delivery

Short description: Methods for delivering drugs to target sites

A nasal spray bottle being demonstrated.

Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect.[1][2] Principles related to drug preparation, route of administration, site-specific targeting, metabolism, and toxicity are used to optimize efficacy and safety, and to improve patient convenience and compliance.[3][4] Drug delivery is aimed at altering a drug's pharmacokinetics and specificity by formulating it with different excipients, drug carriers, and medical devices.[3][5][6] There is additional emphasis on increasing the bioavailability and duration of action of a drug to improve therapeutic outcomes.[7] Some research has also been focused on improving safety for the person administering the medication. For example, several types of microneedle patches have been developed for administering vaccines and other medications to reduce the risk of needlestick injury.[4][8]

Drug delivery is a concept heavily integrated with dosage form and route of administration, the latter sometimes being considered part of the definition.[9] While route of administration is often used interchangeably with drug delivery, the two are separate concepts. Route of administration refers to the path a drug takes to enter the body,[10] whereas drug delivery also encompasses the engineering of delivery systems and can include different dosage forms and devices used to deliver a drug through the same route.[11] Common routes of administration include oral, parenteral (injected), sublingual, topical, transdermal, nasal, ocular, rectal, and vaginal, however, drug delivery is not limited to these routes and there may be several ways to deliver medications through other routes.[12]

Since the approval of the first controlled-release formulation in the 1950s, research into new delivery systems has been progressing, as opposed to new drug development which has been declining.[13][14][15] Several factors may be contributing to this shift in focus. One of the driving factors is the high cost of developing new drugs. A 2013 review found the cost of developing a delivery system was only 10% of the cost of developing a new pharmaceutical.[16] A more recent study found the median cost of bringing a new drug to market was $985 million in 2020, but did not look at the cost of developing drug delivery systems.[17] Other factors that have potentially influenced the increase in drug delivery system development may include the increasing prevalence of both chronic and infectious diseases,[15][18] as well as a general increased understanding of the pharmacology, pharmacokinetics, and pharmacodynamics of many drugs.[3]

## Contents

* 1 Current efforts
* 1.1 The relation between nanomaterial and drug delivery
* 1.2 Targeted delivery
* 1.3 Controlled-release formulations
* 1.4 Modulated drug release and zero-order drug release
* 1.5 Delivery of biologic drugs
* 1.6 Nanoparticle drug delivery
* 2 See also
* 3 References
* 4 External links

## Current efforts

Current efforts in drug delivery are vast and include topics such as controlled-release formulations, targeted delivery, nanomedicine, drug carriers, 3D printing, and the delivery of biologic drugs.[19][20]

### The relation between nanomaterial and drug delivery

Nanotechnology is a broad field of research and development that deals with the manipulation of matter at the atomic or subatomic level. It is used in fields such as medicine, energy, aerospace engineering, and more. One of the applications of nanotechnology in drug delivery. This is a process by which nanoparticles are used to carry and deliver drugs to a specific area in the body. There are several advantages of using nanotechnology for drug delivery, including precise targeting of specific cells, increased drug potency, and lowered toxicity to the cells that are targeted. Nanoparticles can also carry vaccines to cells that might be hard to reach with traditional delivery methods. However, there are some concerns with the use of nanoparticles for drug delivery. Some studies have shown that nanoparticles may contribute to the development of tumors in other parts of the body. There is also growing concern that nanoparticles may have harmful effects on the environment. Despite these potential drawbacks, the use of nanotechnology in drug delivery is still a promising area for future research.[21]

### Targeted delivery

Targeted drug delivery is the delivery of a drug to its target site without having an effect on other tissues.[22] Interest in targeted drug delivery has grown drastically due to its potential implications in the treatment of cancers and other chronic diseases.[23][24][25] In order to achieve efficient targeted delivery, the designed system must avoid the host's defense mechanisms and circulate to its intended site of action.[26] A number of drug carriers have been studied to effectively target specific tissues, including liposomes, nanogels, and other nanotechnologies.[20][23][27]

### Controlled-release formulations

Controlled or modified-release formulations alter the rate and timing at which a drug is liberated, in order to produce adequate or sustained drug concentrations.[28] The first controlled-release (CR) formulation that was developed was Dexedrine in the 1950s.[13] This period of time saw more drugs being formulated as CR, as well as the introduction of transdermal patches to allow drugs to slowly absorb through the skin.[29] Since then, countless other CR products have been developed to account for the physiochemical properties of different drugs, such as depot injections for antipsychotics and sex hormones that require dosing once every few months.[30][31]

Since the late 1990s, most of the research around CR formulations has been focused on implementing nanoparticles to decrease the rate of drug clearance.[13][29]

### Modulated drug release and zero-order drug release

Many scientists worked to create oral formulations that could maintain a constant drug level because of the ability of drug release at a zero-order rate.blood's concentration. However, a few physiological restrictions made it challenging to create such oral formulations. First, because the lower parts of the intestine have a decreased capacity for absorption, the medication absorption typically declines as an oral formulation moves from the stomach to the intestine. The decreased drug amount released from the formulation over time frequently made this condition worse. Phenylpropanolamine HCl release from was the only instance of sustaining consistent blood concentration for roughly 16 hours.[32]

### Delivery of biologic drugs

Pharmaceutical preparations containing peptides, proteins, antibodies, genes, or other biologic components often face absorption issues due to their large sizes or electrostatic charges, and may be susceptible to enzymatic degradation once they have entered the body.[3][11] For these reasons, recent efforts in drug delivery have been focused on methods to avoid these issues through the use of liposomes, nanoparticles, fusion proteins, protein-cage nanoparticles, exploiting routes for the delivery of biologicals that toxins use and many others.[3][33][34][35][36] Intracellular delivery of macromolecules by chemical carriers is most advanced for RNA, as known from RNA-based COVID-19 vaccines, while proteins have also been delivered into cells in vivo and DNA is routinely delivered in vitro.[37][38][39] Among the various routes of administration the oral route is most favored by patients. For most biologic drugs, however, oral bioavailability is too low to reach a therapeutic level. Advanced delivery systems such as formulations containing permeation enhancers or enzyme inhibitors, lipid-based nanocarriers and microneedles will likely enhance oral bioavailability of these drugs sufficiently.[40][41]

### Nanoparticle drug delivery

Drug delivery systems have been around for many years, but there are a few recent applications of drug delivery that warrant 1\. Drug delivery to the brain: Many drugs can be harmful when administered systemically; the brain is very sensitive to medications and can easily cause damage if a drug is administered directly into the bloodstream. As new drug formulations are being developed for brain diseases, including Alzheimer’s disease and Parkinson’s disease, researchers are working on ways to deliver drugs into the brain that do not cause damage to healthy tissue. For example, scientists have developed nanoparticles that can cross the protective blood-brain barrier and deliver drugs directly to the brain.[42][43]

## See also

* Acoustic targeted drug delivery
* Asymmetric membrane capsule
* Bioavailability
* Bovine submaxillary mucin coatings
* Chemotactic drug-targeting
* Drug delivery to the brain
* Drug carrier
* Magnetic drug delivery
* Neural drug delivery systems
* Retrometabolic drug design
* Self-microemulsifying drug delivery system
* Stretch-triggered drug delivery
* Tecrea
* Thin film drug delivery

## References

1. ↑ "Drug Delivery Systems (definition)". http://www.reference.md/files/D016/mD016503.html.
2. ↑ Rayaprolu, Bindhu Madhavi; Strawser, Jonathan J.; Anyarambhatla, Gopal (2018-10-03). "Excipients in parenteral formulations: selection considerations and effective utilization with small molecules and biologics" (in en). Drug Development and Industrial Pharmacy 44 (10): 1565–1571. doi:10.1080/03639045.2018.1483392. ISSN 0363-9045. PMID 29863908. https://www.tandfonline.com/doi/full/10.1080/03639045.2018.1483392.
3. ↑ 3.0 3.1 3.2 3.3 3.4 Tiwari, Gaurav; Tiwari, Ruchi; Sriwastawa, Birendra; Bhati, L; Pandey, S; Pandey, P; Bannerjee, Saurabh K (2012). "Drug delivery systems: An updated review". International Journal of Pharmaceutical Investigation 2 (1): 2–11. doi:10.4103/2230-973X.96920. ISSN 2230-973X. PMID 23071954.
4. ↑ 4.0 4.1 Li, Junwei; Zeng, Mingtao; Shan, Hu; Tong, Chunyi (2017-08-23). "Microneedle Patches as Drug and Vaccine Delivery Platform" (in en). Current Medicinal Chemistry 24 (22): 2413–2422. doi:10.2174/0929867324666170526124053. PMID 28552053. http://www.eurekaselect.com/152718/article.
5. ↑ Tekade, Rakesh K., ed (30 November 2018). Basic fundamentals of drug delivery. Academic Press. ISBN 978-0-12-817910-9. OCLC 1078149382.
6. ↑ Allen, T. M. (2004-03-19). "Drug Delivery Systems: Entering the Mainstream" (in en). Science 303 (5665): 1818–1822. doi:10.1126/science.1095833. ISSN 0036-8075. PMID 15031496. Bibcode: 2004Sci...303.1818A. https://www.science.org/doi/10.1126/science.1095833.
7. ↑ Singh, Akhand Pratap; Biswas, Arpan; Shukla, Aparna; Maiti, Pralay (2019-08-30). "Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles" (in en). Signal Transduction and Targeted Therapy 4 (1): 33. doi:10.1038/s41392-019-0068-3. ISSN 2059-3635. PMID 31637012.
8. ↑ Kim, Yeu-Chun; Park, Jung-Hwan; Prausnitz, Mark R. (November 2012). "Microneedles for drug and vaccine delivery" (in en). Advanced Drug Delivery Reviews 64 (14): 1547–1568. doi:10.1016/j.addr.2012.04.005. PMID 22575858.
9. ↑ Nahler, Gerhard (2017). "D". Dictionary of Pharmaceutical Medicine. Springer, Cham. pp. 96. doi:10.1007/978-3-319-50669-2_4. ISBN 978-3-319-50669-2. https://link.springer.com/chapter/10.1007/978-3-319-50669-2_4.
10. ↑ "route of administration - definition of route of administration in the Medical dictionary - by the Free Online Medical Dictionary, Thesaurus and Encyclopedia.". 2011-06-12. http://medical-dictionary.thefreedictionary.com/route+of+administration.
11. ↑ 11.0 11.1 Jain, Kewal K. (2020), Jain, Kewal K., ed., "An Overview of Drug Delivery Systems" (in en), Drug Delivery Systems, Methods in Molecular Biology (New York, NY: Springer New York) 2059: pp. 1–54, doi:10.1007/978-1-4939-9798-5_1, ISBN 978-1-4939-9797-8, PMID 31435914, http://link.springer.com/10.1007/978-1-4939-9798-5_1, retrieved 2021-04-20
12. ↑ "COMMON ROUTES OF DRUG ADMINISTRATION". https://media.lanecc.edu/users/driscolln/RT114/Medication_Administration/Intro_Pharmacology/Intro_Pharmacology8.html?.
13. ↑ 13.0 13.1 13.2 Park, Kinam (September 2014). "Controlled drug delivery systems: Past forward and future back" (in en). Journal of Controlled Release 190: 3–8. doi:10.1016/j.jconrel.2014.03.054. PMID 24794901.
14. ↑ Scannell, Jack W.; Blanckley, Alex; Boldon, Helen; Warrington, Brian (March 2012). "Diagnosing the decline in pharmaceutical R&D efficiency" (in en). Nature Reviews Drug Discovery 11 (3): 191–200. doi:10.1038/nrd3681. ISSN 1474-1776. PMID 22378269. http://www.nature.com/articles/nrd3681.
15. ↑ 15.0 15.1 ltd, Research and Markets. "Pharmaceutical Drug Delivery Market Forecast to 2027 - COVID-19 Impact and Global Analysis by Route of Administration; Application; End User, and Geography" (in english). https://www.researchandmarkets.com/reports/5067620/pharmaceutical-drug-delivery-market-forecast-to.
16. ↑ He, Huining; Liang, Qiuling; Shin, Meong Cheol; Lee, Kyuri; Gong, Junbo; Ye, Junxiao; Liu, Quan; Wang, Jingkang et al. (2013-12-01). "Significance and strategies in developing delivery systems for bio-macromolecular drugs" (in en). Frontiers of Chemical Science and Engineering 7 (4): 496–507. doi:10.1007/s11705-013-1362-1. ISSN 2095-0187. https://doi.org/10.1007/s11705-013-1362-1.
17. ↑ Wouters, Olivier J.; McKee, Martin; Luyten, Jeroen (2020-03-03). "Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018" (in en). JAMA 323 (9): 844–853. doi:10.1001/jama.2020.1166. ISSN 0098-7484. PMID 32125404.
18. ↑ PricewaterhouseCoopers. "Chronic diseases and conditions are on the rise" (in en-gx). https://www.pwc.com/gx/en/industries/healthcare/emerging-trends-pwc-healthcare/chronic-diseases.html.
19. ↑ Li, Chong; Wang, Jiancheng; Wang, Yiguang; Gao, Huile; Wei, Gang; Huang, Yongzhuo; Yu, Haijun; Gan, Yong et al. (2019-11-01). "Recent progress in drug delivery" (in en). Acta Pharmaceutica Sinica B 9 (6): 1145–1162. doi:10.1016/j.apsb.2019.08.003. ISSN 2211-3835. PMID 31867161.
20. ↑ 20.0 20.1 "Drug Delivery Systems". https://www.nibib.nih.gov/science-education/science-topics/drug-delivery-systems-getting-drugs-their-targets-controlled-manner.
21. ↑ J. Wang, Y. Li, G. Nie, Multifunctional biomolecule nanostructures for cancer therapy, Nat. Rev. Mat. 6 (2021) 766–783
22. ↑ Tekade, Rakesh K.; Maheshwari, Rahul; Soni, Namrata; Tekade, Muktika; Chougule, Mahavir B. (2017-01-01). "Nanotechnology for the Development of Nanomedicine" (in en). Nanotechnology-Based Approaches for Targeting and Delivery of Drugs and Genes: 3–61. doi:10.1016/B978-0-12-809717-5.00001-4. ISBN 9780128097175. https://www.sciencedirect.com/science/article/pii/B9780128097175000014.
23. ↑ 23.0 23.1 Madhusudana Rao, Kummara; Krishna Rao, Kummari S.V.; Ha, Chang-Sik (2018-01-01). "Functional stimuli-responsive polymeric network nanogels as cargo systems for targeted drug delivery and gene delivery in cancer cells" (in en). Design of Nanostructures for Theranostics Applications: 243–275. doi:10.1016/B978-0-12-813669-0.00006-3. ISBN 9780128136690. https://www.sciencedirect.com/science/article/pii/B9780128136690000063.
24. ↑ Patra, Jayanta Kumar; Das, Gitishree; Fraceto, Leonardo Fernandes; Campos, Estefania Vangelie Ramos; Rodriguez-Torres, Maria del Pilar; Acosta-Torres, Laura Susana; Diaz-Torres, Luis Armando; Grillo, Renato et al. (December 2018). "Nano based drug delivery systems: recent developments and future prospects" (in en). Journal of Nanobiotechnology 16 (1): 71. doi:10.1186/s12951-018-0392-8. ISSN 1477-3155. PMID 30231877.
25. ↑ Amidon, Seth; Brown, Jack E.; Dave, Vivek S. (August 2015). "Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches" (in en). AAPS PharmSciTech 16 (4): 731–741. doi:10.1208/s12249-015-0350-9. ISSN 1530-9932. PMID 26070545.
26. ↑ Bertrand, Nicolas; Leroux, Jean-Christophe (2012-07-20). "The journey of a drug-carrier in the body: An anatomo-physiological perspective" (in en). Journal of Controlled Release 161 (2): 152–163. doi:10.1016/j.jconrel.2011.09.098. ISSN 0168-3659. PMID 22001607. https://www.sciencedirect.com/science/article/abs/pii/S0168365911009527.
27. ↑ Rudokas, Mindaugas; Najlah, Mohammad; Alhnan, Mohamed Albed; Elhissi, Abdelbary (2016). "Liposome Delivery Systems for Inhalation: A Critical Review Highlighting Formulation Issues and Anticancer Applications" (in en). Medical Principles and Practice 25 (2): 60–72. doi:10.1159/000445116. ISSN 1011-7571. PMID 26938856.
28. ↑ Perrie, Yvonne (2012). Pharmaceutics- Drug Delivery and Targeting. FASTtrack. pp. 1–19. ISBN 978-0-85711-059-6.
29. ↑ 29.0 29.1 Yun, Yeon Hee; Lee, Byung Kook; Park, Kinam (December 2015). "Controlled Drug Delivery: Historical perspective for the next generation" (in en). Journal of Controlled Release 219: 2–7. doi:10.1016/j.jconrel.2015.10.005. PMID 26456749.
30. ↑ Lindenmayer, Jean-Pierre; Glick, Ira D.; Talreja, Hiteshkumar; Underriner, Michael (July 2020). "Persistent Barriers to the Use of Long-Acting Injectable Antipsychotics for the Treatment of Schizophrenia" (in en). Journal of Clinical Psychopharmacology 40 (4): 346–349. doi:10.1097/JCP.0000000000001225. ISSN 1533-712X. PMID 32639287. https://dx.doi.org/10.1097/JCP.0000000000001225.
31. ↑ Mishell, D. R. (May 1996). "Pharmacokinetics of depot medroxyprogesterone acetate contraception". The Journal of Reproductive Medicine 41 (5 Suppl): 381–390. ISSN 0024-7758. PMID 8725700. https://pubmed.ncbi.nlm.nih.gov/8725700.
32. ↑ J.-C. Liu, M. Farber, Y.W. Chien, Comparative release of phenylpropanolamine HCl from long-acting appetite suppressant products: Acutrim vs, Dexatrim. Drug Develop. and Indus. Pharm. 10 (1984) 1639–1661.
33. ↑ Strohl, William R. (January 2018). "Current progress in innovative engineered antibodies" (in en). Protein & Cell 9 (1): 86–120. doi:10.1007/s13238-017-0457-8. ISSN 1674-800X. PMID 28822103.
34. ↑ Marschall, Andrea L J; Frenzel, André; Schirrmann, Thomas; Schüngel, Manuela; Dübel, Stefan (2011). "Targeting antibodies to the cytoplasm". mAbs 3 (1): 3–16. doi:10.4161/mabs.3.1.14110. ISSN 1942-0862. PMID 21099369.
35. ↑ "The archaeal Dps nanocage targets kidney proximal tubules via glomerular filtration". Journal of Clinical Investigation 129 (9): 3941–3951. September 2019. doi:10.1172/JCI127511. PMID 31424427.
36. ↑ "Targeting the Inside of Cells with Biologicals: Toxin Routes in a Therapeutic Context". BioDrugs 37 (2): 181–203. 2023. doi:10.1007/s40259-023-00580-y. PMID 36729328.
37. ↑ Zuris, John A; Thompson, DB; Shu, Y; Guilinger, JP; Bessen, JL; Hu, JH; Maeder, ML; Joung, JK et al. (Jan 2015). "Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo". Nat Biotechnol 33 (1): 73–80. doi:10.1038/nbt.3081. PMID 25357182.
38. ↑ Schoenmaker, Linde; Witzigmann, D; Kulkarni, JA; Verbeke, R; Kersten, G; Jiskoot, W; Crommelin, DJA (April 2021). "mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability". Int J Pharm 601 (120586): 120586. doi:10.1016/j.ijpharm.2021.120586. PMID 33839230.
39. ↑ Marschall, Andrea L J (October 2021). "Targeting the Inside of Cells with Biologicals: Chemicals as a Delivery Strategy". BioDrugs 25 (6): 643–671. doi:10.1007/s40259-021-00500-y. PMID 34705260.
40. ↑ Haddadzadegan, S; Dorkoosh, F; Bernkop-Schnürch, A (2022). "Oral delivery of therapeutic peptides and proteins: Technology landscape of lipid-based nanocarriers". Adv Drug Deliv Rev 182: 114097. doi:10.1016/j.addr.2021.114097. PMID 34999121.
41. ↑ "Smart hydrogels for advanced drug delivery systems". International Journal of Molecular Sciences 23 (7): 3665. 2022. doi:10.3390/ijms23073665. PMID 35409025.
42. ↑ D.S.W. Benoit, C.T. Overby, K.R. Sims Jr., M.A. Ackun-Farmmer, Drug delivery systems, in: W.R. Wagner, S.E. Sakiyama-Elbert, G. Zhang, M.J. Yaszemski (Eds.), Biomaterials Science (Fourth Edition), Academic Press, 2020, pp. 1237–1266 (Ch. 1232.1235.1212).
43. ↑ Teleanu, Daniel; Chircov, Cristina; Grumezescu, Alexandru; Volceanov, Adrian; Teleanu, Raluca (2018-12-11). "Blood-Brain Delivery Methods Using Nanotechnology" (in en). Pharmaceutics 10 (4): 269. doi:10.3390/pharmaceutics10040269. ISSN 1999-4923. PMID 30544966.

## External links

* Article in Chemical and Engineering News

* v
* t
* e

Routes of administration, dosage forms

Oral|

| Digestive
tract (enteral)|

| Solids|

* Pill
* Tablet
* Capsule
* Pastille
* Time release technology
* Osmotic delivery system (OROS)

|
|

Liquids|

* Decoction
* Elixir
* Electuary
* Emulsion
* Extended-release syrup
* Effervescent powder or tablet
* Herbal tea
* Hydrogel
* Molecular encapsulation
* Powder
* Softgel
* Solution
* Suspension
* Syrup
* Syrup Concentrate for dilution and/or addition of carbonated water
* Tincture

Buccal (sublabial),
sublingual|

| Solids|

* Orally disintegrating tablet (ODT)
* Film
* Lollipop
* Sublingual drops
* Lozenges
* Effervescent buccal tablet
* Chewing gum

|

Liquids|

* Mouthwash
* Toothpaste
* Ointment
* Oral spray

Respiratory
tract|

| Solids|

* Smoking device
* Dry-powder inhaler (DPI)

|
|

Liquids|

* Anaesthetic vaporizer
* Vaporizer
* Nebulizer
* Metered-dose inhaler (MDI)

Gas|

* Oxygen mask and Nasal cannula
* Oxygen concentrator
* Anaesthetic machine
* Relative analgesia machine

Ophthalmic,
otologic, nasal]]|

* Nasal spray
* Ear drops
* Eye drops
* Ointment
* Hydrogel
* Nanosphere suspension
* Insufflation
* Mucoadhesive microdisc (microsphere tablet)

Urogenital|

* Ointment
* Pessary (vaginal suppository)
* Vaginal ring
* Vaginal douche
* Intrauterine device (IUD)
* Extra-amniotic infusion
* Intravesical infusion

Rectal (enteral)|

* Ointment
* Suppository
* Enema
* Solution
* Hydrogel
* Murphy drip
* Nutrient enema

Dermal|

* Ointment
* Topical cream
* Topical gel
* Liniment
* Paste
* Film
* DMSO drug solution
* Electrophoretic dermal delivery system
* Hydrogel
* Liposomes
* Transfersome vesicles
* Cream
* Lotion
* Lip balm
* Medicated shampoo
* Dermal patch
* Transdermal patch
* Contact (rubbed into break in the skin)
* Transdermal spray
* Jet injector

Injection,
infusion<br />(into tissue/blood)

| Skin|

* Intradermal
* Subcutaneous
* Transdermal implant

|
|

Organs|

* Intracavernous
* Intravitreal
* Intra-articular injection
* Transscleral

Central nervous system|

* Intracerebral
* Intrathecal
* Epidural

Circulatory,
musculoskeletal|

* Intravenous
* Intracardiac
* Intramuscular
* Intraosseous
* Intraperitoneal
* Nanocell injection
* Patient-controlled analgesia pump
* PIC line

* v
* t
* e

Topics in medicinal chemistry

* ADME
* Bioavailability
* Chemogenomics
* Drug class
* Drug delivery
* Drug design
* Drug discovery
* Drug targeting
* Enzyme inhibitor
* Ligand efficiency
* Mechanism of action
* Mode of action
* New chemical entity
* Pharmacodynamics
* Pharmacokinetics
* Pharmacology
* Pharmacophore
* Quantitative structure-activity relationship

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