Colloidal Systems

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Syed Rizvi	+ 1246 word(s)	1246	2021-02-15 13:10:34	\|
2	format correct	Catherine Yang	-1 word(s)	1245	2021-02-19 03:24:08	\|

This entry is adapted from the peer-reviewed paper 10.3390/ph14020108

Preparing a suitable formulation for parenteral administration is already a difficult task; this, coupled with poor water-soluble new chemical entity (NCE), complicates this situation even further. Making a micro/nano emulsion with a suitable surfactant not only increases the drug solubility but also the cell membrane permeability. This succinct entry delves into various aspects of biphasic micro/nano emulsion systems for parenteral drug delivery including the structure of the biphasic colloidal systems, characterization parameters, stability issues, regulatory considerations, and applications in life sciences.

drug delivery natural surfactants self-assembled systems drug solubility

1. Introduction

Poorly water-soluble molecules are a challenging problem in the development of suitable pharmaceutical drug formulation. This situation gets further complicated by the fact that most of the newly developed drugs exhibit poor solubility in organic media as well. Consequently, erratic absorption characteristics and low systemic bioavailability are typical issues with poorly water-soluble drugs ^[1]^[2]. The parenteral route of administration (viz. intravenous, intradermal, intramuscular, intraarterial, subcutaneous, etc.), offers a significantly high absorption profile and hence enhanced bioavailability ^[3]. Owing to the low solubility of drugs, it is impossible and actually dangerous to administer solutions intravenously since it can potentially precipitate and clog the vessel ^[2]. Drug delivery scientists have used various formulation approaches to deal with problems associated with the delivery of hydrophobic drugs via the parenteral route ^[3]. The term parenteral is coined out of two words that are Greek in origin, viz. “para” meaning besides and “enteron” meaning gut. Thus, routes of drug administration that bypass the gastrointestinal tract are referred to as parenteral routes of drug delivery. The most critical method of drug delivery is the I.V. (intravenous) route and widely used heterogeneous systems for this route are simple oil-in-water (o/w) emulsions and multiple water-in-oil-in-water (w/o/w) formulations ^[4].

The traditional, and most common, approaches for parenteral delivery of poorly soluble drugs involve complexation, solubilization of hydrophobic agents in micelles and liposomes as drug carrier systems, among a few others. Although the aforementioned approaches are used for hydrophobic drug delivery, they have several limitations hindering the employment of their full potential. Cyclodextrins are expensive and may exhibit poor complexation with the drug under consideration, limited micellar solubilization capacity and complexity coupled with the high cost of the manufacturing process of liposomes ^[3]. Therefore, there is a growing need to improve formulation strategies to improve the parenteral delivery of hydrophobic drugs.

In the pharmaceutical arena, emulsions, as well as micro-emulsions, are widely accepted carriers for the delivery of both lipophilic (hydrophobic) and lipophobic drugs, including the ones with low permeability. Lately, micro-nano-emulsions have acquired increased focus in pharma applications as drug carriers ^[4], since they have great potential to deal with problems that are related to drug delivery of poorly water and also lipid-soluble drugs ^[5]. This brief and succinct review focuses on the diverse aspects of submicron emulsions and nano-suspensions including the structure of colloidal systems, scientific and regulatory considerations in development, FDA approved colloidal systems for parenteral delivery, and key characterization techniques needed for the successful approval of these colloidal systems. Finally, the application of these carrier systems as promising formulation approaches in parenteral drug delivery, including Total Parenteral Nutrition, Vaccine Delivery, Long-Acting Injectable Therapy, and Anti-Cancer Drugs and Diagnostic Agents, will also be highlighted.

2. Applications of Colloidal Carriers

2.1. Total Parenteral Nutrition

Energy deficit is a common problem among ICU patients. Parenteral nutrition (PN) can improve caloric delivery to critically ill patients whether used for the short-term or the long-term. In artificial nutrition, lipids are an important source of calories. ILEs (intravenous lipid emulsions) are one of the vital components of PN regimen as they provide a dense source of energy, as well as essential and conditionally essential fatty acids. Commercially available ILEs are complex mixtures of oil-in-water. Emulsification allows the lipid phase and aqueous phase to co-exist at a lower surface tension as a homogeneous dispersion of fat globules in water. ILEs contain thousands of fat globules per mL, with a mean diameter of ≈0.25–0.5 μm. ILEs differ from each other in terms of oil source, fatty acid composition, lipid concentration and other ingredients such as vitamins. Two common ILE formulation delivery systems are the 2-in-1 system, with two macro-nutrients (glucose, amino acids) and all micronutrients in a single bag (ILE separate), and the 3-in-1 system (total nutrient admixture), with three macronutrients and all micronutrients in a single bag. Thus, PN alone or in combination with enteral nutrition (EN) can improve caloric delivery to all critically ill patients ^[6]^[7].

2.2. Vaccine Delivery

Vaccination is a remarkable means of prevention of infectious diseases thereby contributing significantly to an increase in life expectancy. Despite these exceptional achievements, there is still an on-going requirement to improve vaccine delivery in order to combat infectious diseases. Currently, most vaccines are administered via invasive routes. Parenteral route of vaccine administration can trigger systemic immune response ^[8]. The inability of vaccine candidates to invoke suitable immune responses leads to failed vaccine development ^[9]. There is a necessity for the development of potent as well as safe adjuvants to deliver new generations of vaccines against infectious (e.g., pneumonia) and non-infectious (e.g., cancer) diseases ^[10]^[11]. The invention of Baker et al. provides composition and methods to stimulate immune responses using nanoemulsion and an inactivated pathogen via mucosal delivery ^[12]. Squalene o/w emulsion containing influenza vaccine was approved in Italy in 1997 ^[8].

2.3. Long-Acting Injectable (LAI) Therapy

Long-acting injectable formulations help sustain the therapeutic action of drugs in the body over desired time intervals. There is an increased frequency of administration of drugs that are susceptible to rapid in vivo clearance leading to poor patient compliance. Thus, the development of controlled release strategies allows extended systemic exposure on the administration of a single dose ^[13]. Key factors affecting drug release kinetics are variability in the structure of the tissue, physiology of the recipient, rate of injection and technology format ^[14]. LAIs are administered in the proximity of the affected tissue directing drug exposure over prolonged periods of time. LAI technology platforms include: (i) microencapsulation, (ii) in-situ forming depots (gels/implants) and (iii) molecular and particulate delivery systems. Invega Trinza^® and Invega Sustenna^® are sterile nanosuspensions of paliperidone palmitate that were first registered with a dose of 150 mg/human monthly and 525 mg/human every three months, respectively ^[13].

2.4. Anti-Cancer Drugs and Diagnostic Agents

Conventional chemotherapeutic agents to diagnose and treat cancer attack tumor cells and healthy body cells non-specifically, leading to life-threatening side effects. Encapsulation of these agents in the nanoparticle matrix as nanosuspensions has shown encouraging results in the specific targeting of anti-cancer drugs and diagnostic agents for the targeting of cancer cells ^[15]. In addition, many of the currently used anti-cancer drugs have low aqueous solubility and require use of toxic co-solvents such as cremophor to aid solubility. Development of such anti-cancer drugs as nanosuspensions avoids the use of toxic solvents to enhance solubility and use of biodegradable polymers greatly enhances safety profile of these drug loaded nanoparticle systems, Table 1 ^[16].

Table 1. Over-view of parenteral nanomedicines approved by USFDA (https://www.accessdata.fda.gov/scripts/cder/daf/).

Dosage Form	Sponsor	Indication	Active Ingredient	Route of Administration
Paclitaxel Injection, USP	Grand Pharma Ltd.	Anti-tumor	Paclitaxel	Intravenous
Diprivan^®	Fresenius Kabi USA LLC	General anesthetic and sedation drug	Propofol	Intravenous
ZYPREXA^® Intramuscular Injection	Lilly	Treatment of Schizophrenia	Olanzapine	Intramuscular
Phytonadione Injection, USP	International Medication Systems Ltd.	Treatment of Hypoprothrombinemia	Phytonadione	Intravenous/Intramuscular
Abraxane^® for Injectable Suspension, USP	Abraxis Bioscience	Treatment of Metastatic Breast Cancer	Paclitaxel	Intravenous
Invega sustenna^®	Janssen Pharms	Antipyschotic	Paliperidone Palmitate	Intramuscular
Methylprednisolone Acetate Injectable Suspension, USP	Sandoz Inc.	Anti-inflammatory	Methylprednisolone Acetate	Intramuscular, Intraarticular, Intralesional

References

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