Drug Delivery Systems

To acheive marketing approval, a molecule  undergoes different development  phases and a variety of studies need to  be carried out. A new molecule typically  involves preclinical testing in animals followed  by clinical trials in humans, after  which the application is submitted to regulatory  agencies for review. In case of new  delivery system, since drug molecule is already  known, there is no need to carry out  full clinical trials.  

Types of Drug Delivery Systems  

Current drug delivery systems can be categorised  as Oral, Pulmonary, Transdermal, Injectables,  etc.  

A. Oral Drug Delivery Systems  

Oral route is one of the most extensively  used routes of drug administration because  of its obvious advantages of ease  of administration, improved patient compliance,  and convenience. In immediate  release (IR) dosage forms, there is little  or no control over release of drug from  the dosage form, which most often results  in constantly changing, unpredictable,  and often sub- or supra- therapeutic  plasma concentration. Modified  release (MR) dosage form refers to a  dosage form for which the drug-release  characteristics of time course and/or location  are chosen to accomplish therapeutic  or convenience objectives not offered  by conventional dosage forms.  Extended release (ER) and delayed release  (DR) dosage forms are two types of  MR dosage forms.  

ER dosage forms are formulated to make  the drug available over an extended period  after ingestion. This allows a reduction  in dosage frequency compared to the  drug presented as a conventional dosage  form (e.g., an IR dosage form). These  products typically provide numerous benefits,  including greater effectiveness in  the treatment of chronic conditions, reduced  side effects, greater convenience,  and higher levels of patient compliance  due to a simplified dosing schedule. The  term controlled release (CR) and extended  release are often used interchangeably.  A number of design options are available  to control or modulate the drug  release from a dosage form. Majority of  the oral dosage forms fall in the category  of matrix, reservoir, osmotic systems,  or ion exchange resins. DR dosage forms  release the drug at a time other than immediately  following oral administration.  

B. Pulmonary Delivery Systems  

Pulmonary delivery has been until now primarily  used for the treatment of respiratory  disease. Recently, the lungs' natural  ability to transfer molecules into the blood  stream has been utilised for delivering  drugs to the systemic circulation. This  method is a noninvasive alternative to the  painful injections and can lead to rapid  onset of action and good bioavailability.  Inhalation devices broadly fall into three  categories: Pressurised metered-dose inhalers  (MDIs), nebulisers, and dry powder  inhalers (DPIs). MDIs contain drugs as a  solution or a suspension of fine particles  in a liquefied propellant held under high  pressure. The drug is emitted through an  orifice from a metering valve. Nebulizers,  on the other hand, do not require propellants  and can generate large quantities of  small droplets capable of penetrating into  the lung. DPI is a device that delivers medication  to the lungs in the form of a dry  powder and requires some procedure to  allow a measured dose of powder to be  ready for the patient to take. The drug is  typically held either in a capsule for manual  loading or a proprietary form from inside  the inhaler itself. Once loaded or actuated,  the patient puts the mouthpiece  of the inhaler into their mouth and takes  a deep inhalation, thereby delivering the  drug.  

C. Transdermal Drug Delivery Systems  

Systemic delivery of drugs via transdermal  route has generated a considerable  interest during the last decade. Transdermal  drug delivery systems (TDDS) deliver  drugs through the skin into the systemic  circulation at a predetermined rate,  thereby avoiding metabolism in the gastrointestinal  tract and liver. Therefore,  the amount of active ingredient required  for transdermal delivery can be significantly  less than that for oral systems.  TDDS provide constant blood levels for  one to seven days and increased patient  compliance.

D. Injectables  

The research efforts in the field of genomics  are expected to accelerate the discovery of  new therapeutic biomolecules, placing an increased  demand on the development of delivery  systems for these drugs. This class of  drugs are usually characterised by their large  size, fragile nature, short biological half-life,  and limited ability to cross cell membranes.  These properties along with the methods of  administration of biopharmaceuticals can limit  their clinical applications to certain diseased  states that warrant the expense and inconvenience  of frequent injection. Several parenteral  depot formulations based on  biodegradable polymers such as microspheres  and implants have become commercially  available to improve the efficacy and prolong  activity of several peptide and protein drugs.  

Implants can be surgically implanted inside  the body from where the drug release takes  place at a controlled rate and the duration  can be as long as 12 months. Another option  is use of biodegradable implants that  can be injected using a large gauge needle  and they offer the advantage of a single procedure  (no need to remove the implant).  

Injectable MR dosage forms, typically a matrix  is fabricated into an easily injectable form  for administration at the desired tissue site  (e.g., subcutaneously). The dosage form may  be either a solid, gel, or liquid. Solid dosage  forms such as biodegradable microspheres  consisting of poly(lactic-co-glycolic acid)  have been used as an injectable depot delivery  system of small-molecule drugs, peptides,  and proteins. The injectable gels usually  consist of a solvent to dissolve the matrix  and/or the therapeutic agent and they form  an “implant-like” depot upon injection. 

E. Ophthalmic (Ocular) Drug Delivery  Systems  

Recently, there has been increased attention  for ophthalmic drug delivery as  these delivery systems require less frequent  administration than eye drops, allow  continuous drug delivery, and extend  the duration of drug action by enhancement  of corneal absorption. Ocular delivery  systems include viscous solution  and hydrogel delivery systems, ocular inserts  and contact lenses.  

F. Vaginal Drug Delivery  

The vagina has been studied as a favorable  site for the local and systemic delivery  of drugs and this route offers certain  advantages, such as avoidance of gut and  hepatic first pass metabolism, reduction  in gastrointestinal and hepatic side effects,  and local targeting of drugs to the  reproductive organs. Vaginally administered  agents and formulations are mainly  being developed to provide “dual prophylaxis”  for contraception and protection  against microbial infections including AIDS  and other sexually transmitted diseases  (STDs). Drug delivery technologies that  have been used for vaginal drug delivery  include the intravaginal ring (IVR) and  VagiSite bioadhesive technology.  

Future Research and  Conclusions  

As discussed in this article, drugs can be delivered  to a patient through many different  delivery systems, including oral, transdermal,  injection, pulmonary route, etc. With  the sequencing of the human genome,  biotechnology companies are rapidly developing  a large number of peptide- and  protein-based drugs and it is expected that  in the next few years, this category will constitute  a major portion of the new drugs.  These biopharmaceuticals present drug delivery  challenges because these are often  large molecules that degrade rapidly in the  blood stream. Moreover, they have a limited  ability to cross cell membranes and generally  cannot be delivered orally. The possibility  of other routes of administration will  be dictated by the drug, disease state, and  desired site of action. Some sites are easy  to reach such as nasal, buccal, vagina, etc,  while others are more challenging to access,  simplest example being the brain. Gene therapy  is also likely to be one of the most exciting  growth sectors as biotech companies  become involved in drug delivery.  

Nowadays, apart from the research in the  technologies mentioned in this article, individualised  dosing has emerged as one of the  important focus areas. A recent article gives  a very good overview of solid and liquid drug  dosage forms used in personalized medicine.  Solid dosage pen is such a device delivering  a swallowable solid monolithical oral  dosage form containing individual doses.  The device consists of a drug loaded rod  (can be manufactured by an extrusion  method) that can be fed forward.  

Recent advances in the field of micro-fabrication  have opened up the possibility of  developing a new class of programmable  drug delivery systems. One such device is  microchip based delivery system. Chip consists  of an electrolyte impermeable substrate,  which separates the series of reservoir  consisting of the component(s) to be  released. Based on electrochemical reactions,  the membrane disappears and the  drug(s) are then diffused or release from  the reservoir. Their small size and potential  for integration with micro-electronics  coupled with ability to store and release  drug(s) on demand opens up a whole new  world of possibilities in drug delivery.  

In conclusion, the market for drug delivery  systems has come a long way and will  continue to grow at an impressive rate. Today’s  drug delivery technologies enable  the incorporation of drug molecules into  new delivery systems thus, providing numerous  therapeutic and commercial advantages.  A large number of companies  are involved in the development of new  drug delivery systems, which is evident by  an increased number of products in the  market and the number of patents granted  in the recent past. Tomorrow’s drugs will  definitely be more challenging in terms of  the development of delivery systems, and  pharmaceutical scientists will have to be  ready for a difficult task ahead.  

The authors would like to acknowledge Dr.  Pradip Ghosh, Ms. Priyanka Kudyar, Mr. Ankit  Baheti, and Mr. V. Harish Kumar (all from Dr.  Reddy’s Laboratories Ltd.) for their valuable  contributions in preparing this manuscript.