PROMISING PHARMACEUTICAL DELIVERIES

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The market of drug delivery in the United States has shown a  growth rate of 9% annually (134). Presently, this pharmaceutical delivery technology has incorporated nanotechnology in many frontiers. This advanced technology provides targeted delivery of various therapeutic agents. The unique property of nanoparticle based delivery systems is to deliver the drug in a particular tissue or organ. They have the capability to distinguish a diseased cell from a healthy one in the body (135). Such a mechanism will lead to a highly efficient, targeted delivery system, controlled delivery and optimum bioavailability.

1. Brain targeted drug delivery

One of the areas of medicine that can benefit from nanoparticle targeted drug delivery is the central nervous system (CNS). The treatment of CNS diseases is limited due to deficiency of the delivery of therapeutic agents. The main cause is the inefficient delivery of drugs which are unable to reach the desired targets. In order to achieve effective treatment for CNS disorders, it is necessary to transfer therapeutic agents across the blood–brain barrier (BBB) which is a very challenging task even today (136). Nanoparilcle based delivery system can solve this because it can cross the BBB. Additionally, this process may decrease drug leakage and can diminish peripheral toxicity (137, 138). Recently, paclitaxel, anti cancer dug, has been used efficiently for brain cancer using glutathione-coated nanoparticles (139) whereas; paclitaxel alone cannot cross the BBB. It has been noted that aptamer-functionalized PEG-PLGA nanoparticles can improve anti-glioma drug delivery (140). Other than cancer, active therapeutic molecules have been delivered in CNS diseases such as prion disease (141), Alzheimer's disease (142), and antioxidants for the treatment of neurodegenerative diseases (143). However, nanoparticles based delivery systems can cross BBB easily which are creating a lot of hope for the treatment of specific CNS diseases that currently have no cure.

2. Pulmonary drug delivery

Pulmonary drug delivery is an important route of administration for delivery of therapeutic agents especially for peptides and proteins. Several advantages make the lung as an efficient route for drug delivery. The advantages are i) Large absorptive surface area; ii) Human lung is extremely thin, and it is recorded between 0.1 µm – 0.2 µm; iii) It provides an absorptive mucosal membrane; iv) Lung is highly vascular with good blood supply, and  lastly v) this delivery system can eliminate injection. Therefore, pulmonary route of drug delivery shows great promise (144, 145) utilizing two techniques: aerosol inhalation technique and intratracheal instillation (146). Several nanoparticles based delivery systems are being developed for administration by pulmonary route. Eg. a sildenafil-loaded nanoparticle is a promising drug for the therapy of pulmonary arterial hypertension (147). For pulmonary fibrosis and exacerbated lung disease, CNTs allow extensive functionalization and loading of drugs (148). Spray-dried aqueous PLGA nanosuspensions were developed for pulmonary drug delivery which can access the alveolar tissue (149). Antitubercular drugs were encapsulated in poly (DL-lactide-co-glycolide) nanoparticles suitable for nebulization which shows better bioavailability and reduction of dose incidence for better management of pulmonary tuberculosis (150). Presently, pulmonary nanoparticle drug formulations have generated great interest in the pharmaceutical industry, but this is a challenging route of drug administration for new drugs.

3. Ocular drug delivery

The efficacy of ocular drug delivery is influenced by the corneal contact time (151, 152). Therefore, the major challenge for ophthalmic drugs is controlled and sustained delivery (153). Presently, solutions, suspensions and ointment are the most common topical form of drugs which are used regularly for ocular infections. These conventional dosages are used in people suffering from problems such as poor ocular bioavailability due to anatomical and pathophysiological obstruction existing in the eye (154). Currently, dilutable nanoemulsions are powerful drug delivery vehicles for ocular diseases (155,160). Its sustained effect, high penetration ability into the deeper layers of eye makes a better delivery system. Using nanoemulsion, dorzolamide hydrochloride is used for the treatment of glaucoma (155). Nanosuspensions may be included in a hydrogel base or mucoadhesive base or even in ocular inserts. An experiment has been performed to achieve the desired action of polymeric nanosuspensions loaded with the drug. The result shows better sustainability for the release of the drug (156). A polymeric nanosuspension of flurbiprofen and ibuprofen have been successfully formulated using acrylate polymers such as Eudragit RS 100 and Eudragit RL 100 (157-159). Another approach is to immobilize the drug with the help of the nonovehicle (such as liposome) on the exterior of marketable contact lenses (160). Immobilized of levofloxacin liposome’s on NeutrAvidin-coated Hioxifilcon-B contact lenses have been released in this direction. It was noted that approximately 70% drug was free within the initial five hrs and remaining 30% drug discharge occurred over the subsequent 6 days (161). To date, nanoparticle based delivery systems emerged to be an exclusive and so far commercially viable way to combat problems such as reduced bioavailability or other issues of ophthalmologic drugs.

 

4. Oral delivery

Presently, an important research has been performed using nanoparticles as oral drug delivery carriers. Oral delivery of drugs using nanocarriers has revealed better delivery in terms of bioavailability and biodistribution (162). For example, insulin-loaded nanoparticles have conserved insulin activity and decrease in blood glucose level in diabetic rats for up to 14 days following the oral delivery (163). Using lactic-co-glycolic acid nanoparticle, salmon calcitonin (sCT)-loaded oral drug delivery system has been evaluated in vitro and in vivo (164). But, oral protein or peptide delivery still remains to be an issue today because of their poor oral bioavailability.

Nanoparticles can be engineered to distribute a drug directly to the basis for gastrointestinal uptake. These drugs need to be protected from low pH as well as enzymes present in the stomach. The pH-sensitive nanoparticles can be developed from a copolymer (methylacrylic acid and methacyrlate). It may provide a better result for the oral bioavailability of drugs like cyclosporine-which has specific pH inside the gastrointestinal tract. The pH sensitive nanoparticles help the drugs absorption through the Peyer's patches (165).

5. Dermal and transdermal delivery

Nanocarriers are the promising dermal and transdermal pharmaceutical delivery systems. Most prominent nanocarriers such as microemulsions, liposome’s, micron sized, and nanoparticles are in use for dermal and transdermal applications (166). Several nanotechnology based dermal products such as medicated moisturizers, sunscreen are available in the market. The major compounds used for dermal applications are titanium dioxide and zinc oxide. Also, liposomes and niosomes are used in the cosmetic industry as delivery vehicles (167, 168). In addition, nanoemulsions are also used for dermal delivery. Nanoemulsions are nanoscale droplets of one liquid within another (169). From nanoemulsions, we can produce water-like fluids or gels, because emulsions are metastable systems (170). There are several advantages of these gels/water-like fluids, such as i) It can be stabilized to enhance the time before creaming occurs, and therefore, in this way increase the shelf life (171); ii) They are transparent and have bigger surface area because of the tiny particle size, and iii) nano scale dimension of the emulsion has high stability and better suitability to carry drugs (172). Several companies are producing stable nanoemulsions for dermal delivery such as Nanocream® from Sinerga (www.sinerga.it) and NanoGel from Kemira (www.kemira.com). Using lipid nanoparticles, several companies are manufacturing products for increased skin penetration. Muller et al. (173) and Pardeike et al. (174) have listed commercially available products and their ingredients in dermal delivery. Several drugs in this area have a number of limitations due to problems relating to controlled drug release and achieving therapeutic efficacy. Lipid nanocapsules and solid lipid nanoparticles (SLNs) have been developed with increased efficacy. Lipid nanocapsules (LNC) are colloidal carriers which can offer controlled release property as well as better bioavailability for dermal delivery (175). Solid lipid nanoparticles (SLNs) are investigated due to their potential topical delivery, possible skin compartments targeting and controlled release in the skin. It is also reported that in Fluconazole, an antifungal ingredient, nanoparticles optimize the drug retention in the skin (176).

6. Cancer chemotherapy

Conventional chemotherapy in cancer suffers from drawbacks of toxicity and nonspecificity. Nanoparicles are potential carriers for cancer drugs because of the ability to specifically target and hit the cancer cells. Gadolinium neutron-capture therapy (Gd-NCT) for cancer was evaluated by Tokumitsu et al. (177) using gadolinium-loaded nanoparticles. The tumor growth in the nanoparticle governed bunch was considerably suppressed related to that in the gadopentetate solution-administered bunch. Glutaraldehyde cross-linked with chitosan having mitoxantrone antitumor activity was estimated using carcinoma in mice. Mean survival was increased to 50 days (178). Nanoparticle carrier with doxorubicin has been delivered to tumor cell successfully (179-181). An albumin-bound structure was added in doxorubicin where metalloproteinase-2 has been included and new matrix was developed (182) which is a targeted delivery in the unique microenvironment surrounding the tumor cells.  This important nanoparticle carrier drug is in clinical trials (183). Another example is colloidal gold nanoparticles, a sol comprised of nanoparticles of Au (0), which represents a new tool in the field of particle-based tumor-targeted drug delivery (184). Several other delivery systems have been developed such as liposomes, polymeric micelles, dendrimers, superparamagnetic iron oxide crystals, and colloidal gold etc. These carriers utilize both passive and active targeting strategies (185). Drug resistance appears to be one of the main limiting factors for the chemotherapeutic agents, and P-glycoprotein related drug resistance is well understood (186). However, nanoparticle carrier of drugs can solve the P-glycoprotein–mediated resistance problem (187). It is anticipated that the nanoscale drug delivery systems can solve several problems and provide better cancer chemotherapy.

7. Vaccine delivery

Nanoparticles (NPs) have gathered increased attention for their ability to serve as a viable carrier for site specific delivery of vaccines. Several methods now exist for synthesizing different sets of nanoparticles based on the type of vaccines used and delivery mechanism selected (188). As an example, nanocarriers are used for the systemic and mucosal delivery of vaccine (189).  In fact, mucosal vaccine delivery started because mucosal exterior signify the main point of entry for a lot of pathogens (190). This route offer simplified and cost-effective protocol for vaccination with anticipation for improved patient compliance. For mucosal immunization, PLGA nanoparticles have been developed against hepatitis B (191). It is reported that antigen-loaded nanocarriers are able of being dynamically absorbed by antigen-presenting cells which have shown the potential for cancer immunotherapy (192).  Recently, several strategies have been developed which can initiate antigen-specific immune responses. An antibody-mediated delivery of nanoparticle vaccines has been developed for human dendritic cells (193). New technologies are developed for parasite and viral vaccine as well. Viral vaccines using nanoparticle carriers for H6N2 avian influenza virus and HIV vaccine was investigated using poly (2-hydroxyethyl methacrylate) i.e. pHEMA nanoparticle. This work suggests that by means of 100 μg of pHEMA nanoparticles showed decline in virus shedding and improved the immune response (194). In HIV, disease engages the interaction among the viral envelope-protein gp120 and cell receptor CD4. A study has been performed to demonstrate the interaction of HIV-1 gp120 protein to silica NP (195). This study demonstrated that CD4 bound to silica particles recognized and retained high binding affinity for HIV-gp120 (195). For the effective malarial vaccine, recombinant malarial antigen i.e. merozoite surface protein 1 (rMSP1) has been covalently conjugated to polymer-coated quantum dot CdSe/ZnS nanoparticles (QDs) via surface carboxyl groups forming rMSP1-QDs. This shows promising results to improve the immunogenicity of the polypeptide antigens in adjuvant-free immunizations (196). These novel vaccine platforms utilize engineered nanoparticle delivery system which is more efficient and safer than the previous vaccines.

8. Therapeutic nucleic acids

Nucleic acids as drugs have a great future in molecular medicine for gene therapy. Using these therapies, it has been projected that several serious diseases can be treated such as genetic diseases, viral infections or cancer (197). Liposome’s (198), dendrimers (200), biodegradable polymeric nanoparticles (201) and gold nanoparticles (202) have been used for gene therapy.  There are generally two ways of nucleic acids delivery such as encapsulation and conjugation. Nucleic acids like plasmid DNA, RNA, and siRNA can be encapsulated with a nanoparticle (203) or conjugated with the nanoparticle (204-206). One way to link nucleic acids to a nanoparticle, especially DNA, is to modify the surface of the nanoparticle to bring a positive charge. The positive charge of the nanoparticle can bind easily with the negative charge of the DNA. This mechanism is used for liposome and other polymer-mediated nucleic acid transfer (207, 208). Recently, Mendez-Ardoy et al. (209) have developed polycationic amphiphilic cyclodextrin-based nanoparticles which are used for therapeutic gene delivery (IL-12). For siRNA therapeutic delivery, Beloor et al. (210) used arginine-engrafted biodegradable polymer which enhanced accumulation of carrier-siRNA complexes in the tumor tissue. However, there is an urgent need for the generation of a common platform on nanoparticle based delivery systems which can be modified easily to deliver different types of nucleic acids.

Table 1. Approved drugs with nanoparticle-based delivery system which are commercially available

Sl.No	Product name and company name	Nanoparticle based delivery system and Pharmaceutical ingredient	Indication	Delivery route	Reference
1	Abelcet (Enzon ,USA)	Delivery system: Lipid complex Ingredient: Amphotericin B	Fungal infections	Injection (Intravenous route)	221
2	AmBisome (Gilead Science, Japan)	Delivery system: Liposome Ingredient: Amphotericin B	Fungal and protozoal infections	Injection (Intravenous route)	222
3	DaunoXome (Gilead Science, Japan)	Delivery system: Liposome Ingredient: Daunorubicin	Kaposi sarcoma	Injection (Intravenous route)	223
4	Doxil/Caelyx (Ortho Biotech, USA and Schering-Plough,USA)	Delivery system: Liposome Ingredient: Doxorubicin	Cancer, Kaposi sarcoma	Injection (Intravenous route)	224
5	DepoCyt (SkyePharma, UK)	Delivery system: Liposome Ingredient: cytarabine	Cancer	Injection (Intravenous route)	225
6	Epaxal Berna (Berna Biotech, Switzerland)	Delivery system: virosome Ingredient: Hepatitis A Vaccine	Hepatitis A	Injection  (Intravenous route)	226,227
7	Visudyne (QLT Canada and Novartis AG, Switzerland)	Delivery system: Liposome Ingredient: Verteporfin	Age-related macular degeneration	Injection (Intravenous  route)	228
8	Neulasta (Amgen, USA)	Delivery system: Polyethylene glycol (PEG) Ingredient:Granulocyte colony-stimulating factor (GCSF)	neutropenia	Injection (Intravenous or  subcutaneous route)	229
9	Pegasys (Nektar, USA and Hoffmann-La Roche Switzerland)	Delivery system: Polyethylene glycol (PEG) Ingredient: interferon-α 2a	Hepatitis C	Injection (Intravenous or  subcutaneous route)	230, 231
10	PEG-Intron	Delivery system: Polyethylene glycol (PEG) Ingredient: Interferon-α 2b	Hepatitis C	Injection (Intravenous or  subcutaneous route)	232
10	Renagel (Genzyme,USA)	Delivery system: Crosslinked poly(allylamine) resin Ingredient: Sevelamer HCL	Chronic kidney disease	Oral delivery	233
11	Tricor (Abbott Laboratories, USA)	Delivery system: Nanocrystalline Ingredient: fenofibrate	Lipid regulation	Oral delivery	234
12	Abraxane (Abraxis BioScience, USA and AstraZeneca,UK)	Delivery system: Albumin Nanoparticles Ingredient: paclitaxel	Cancer	Injection (Intravenous route)	235
13	Copaxone (TEVA Pharmaceuticals,USA)	Delivery system: L-Glutamic acid, L-alanine, L-lysine, and L-tyrosine copolymer Ingredient: Glatiramer Acetate	Multiple sclerosis	Injection (Intravenous route)	236
14	Estrasorb (NovavaxInc. USA)	Delivery system: micellar nanoparticle Ingredient: estradiol emulsion	Menopausal therapy	Topical	237,238

9. Delivery system coupling to implants

Presently, various implant devices have been prepared which are attached to smart drug delivery systems. Examples of implant devices are biosensors, pacemakers and stents (211). Several intra-ocular devices have been prepared for the delivery of ocular drugs (212). The coupling of drug delivery to sensors has been used for the treatment of diabetes (213) and also to measure oxygen pressure (214). Several scientists are working in this field to develop engineered nanoparticles for the development of the delivery systems coupling to implants.