Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 5  |  Issue : 1  |  Page : 1-10  

Hollow microspheres as a drug carrier: An overview of fabrication and in vivo characterization techniques


University Institute of Pharmacy, Pandit Ravishankar Shukla University, Raipur, Chhattisgarh, India

Date of Web Publication25-Mar-2014

Correspondence Address:
Preeti Kumaran Suresh
University Institute of Pharmacy, Pandit Ravishankar Shukla University, Raipur - 492 010, Chhattisgarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2229-5186.129327

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   Abstract 

Oral controlled release dosage forms encounter several physiological constraints like inability to retain and locate the controlled drug delivery system within the desired region of the gastrointestinal tract (GIT) due to variation in gastric emptying. This leads to non - uniform absorption profile, insufficient drug release and shorter residence time of the dosage form in the stomach. As the fallout of this event, there is incomplete absorption of the drug having absorption window especially, in the upper part of GIT. These considerations have led to the development of oral controlled release dosage forms with gastroretentive properties. Hollow microspheres hold promise as one of the potential approaches for gastric retention. Hollow microspheres are spherical empty particles without core and can remain in the gastric region for prolonged periods. They significantly extend the gastric residence time of drugs, thereby improving bioavailability, reduced the drug waste and improved solubility for drugs that are less soluble at a higher pH environment. This review attempts to bring more insight into recent advances in methods of fabrication techniques and applications of hollow microspheres.

Keywords: Controlled release, floating microspheres, gastric retention, hollow microspheres, low density, oral


How to cite this article:
Kurrey A, Suresh PK, Singh MR. Hollow microspheres as a drug carrier: An overview of fabrication and in vivo characterization techniques. Chron Young Sci 2014;5:1-10

How to cite this URL:
Kurrey A, Suresh PK, Singh MR. Hollow microspheres as a drug carrier: An overview of fabrication and in vivo characterization techniques. Chron Young Sci [serial online] 2014 [cited 2020 Jan 27];5:1-10. Available from: http://www.cysonline.org/text.asp?2014/5/1/1/129327


   Introduction Top


The oral route is the most acceptable mode for the administration of pharmacologically active substance to the systemic circulation. Some drugs have ideal characteristics for good absorption throughout the gastrointestinal tract (GIT), whereas others have difficulties. [1] To achieve the effective oral drug delivery, oral controlled release dosage form have been developed over many decades. They offer considerable therapeutic advantages in terms of ease of administration, reduced dosing frequency, better patient compliance and flexibility in formulation. [2] However, in this approach several physiological difficulties have been encountered due to inability to retain and locate the controlled drug delivery system within the desired region of GIT. These problems are manifested due to variation in gastric emptying, leading to non-uniform absorption profile, insufficient drug release and shorter residence time of the dosage form in the stomach. [3] This leads to incomplete absorption of the drug having absorption window, especially in the upper part of GIT. [4] These considerations have led to the development of oral controlled release dosage form with gastroretentive properties.

The ability of gastroretentive systems to remain in the gastric region for a longer period significantly prolong the gastric retention time of drugs. Improved bioavailability, reduction in drug waste and improvement in solubility of drugs that have limited solubility in high pH environment can be achieved by prolonging gastric retention of drugs. [5],[6]


   Approaches to Gastric Retention Top


Various approaches have been reported to achieve gastric retention of an oral dosage form. These include.

Hydrodynamically balanced systems

In hydrodynamically balanced systems, drug with gel-forming hydrocolloids are meant to remain buoyant over the stomach content. This prolongs gastric retention time and maximizes the amount of drug that reaches its absorption sites. These hydrocolloids on contact with gastric fluid, hydrates and forms a colloid gel barrier around its surface. [7]

Effervescent systems

The gas generating agents such as carbonates (e.g., sodium bicarbonate) and other organic acid (e.g., citric acid and tartaric acid) are utilized in the formation effervescent systems. The density of the present system is reduced due to the production of carbon dioxide by the reaction of gas generating agents with gastric acid, thus allowing the system to float on the gastric fluid. [8]

Low-density systems

Floating systems are based on low density approach. Floating drug delivery systems by virtue of their bulk density lower than gastric fluids (<1 g/ml), float over the gastric fluid and release the drug slowly for a longer period of time. They are prepared by incorporating low-density materials, entrapping oil or air. Most are multiple unit systems and are also called "microballoons" because of their low-density core. [9]

Raft systems

Raft systems upon contact with gastric fluid form a viscous cohesive gel, which swells to form a continuous layer called a raft. Generation of CO 2 by a gel forming solution (e.g. sodium alginate solution containing carbonates or bicarbonates) makes the raft float on gastric fluid. [10]

Bioadhesive or mucoadhesive systems

Bioadhesive systems bind to the gastric epithelial cell surface and extend the residence time of the dosage form in the stomach, thereby facilitating an intimate contact of drug with the biological membrane for prolonged duration. This approach involves the use of bioadhesive polymers such as polycarbophil, carbopol, lectins, chitosan and gliadin. [11]

High-density systems

High-density systems have a density (3 g/ml) far exceeding that of normal stomach contents (1 g/ml) and are thus retained in the fold of the stomach for a longer period of time. This is achieved by coating the drug with heavy inert materials such as barium sulfate, zinc oxide, titanium dioxide, iron powder, etc. [12]


   Hollow Microspheres Top


Hollow microspheres are gastroretentive drug delivery systems based on non-effervescent approach. They are spherical empty particles without core. They possess the unique advantages of multiple unit systems and their center hollow space imparts good floating properties making them promising buoyant systems. These microspheres are free flowing low density powders, having a size less than 200 μm, comprising of either proteins or synthetic polymers. [13] The sustained release of drug from the buoyant systems improves the gastric retention and reduces the fluctuations in plasma drug concentration. [14] The quantity of polymers, the plasticizer-polymer ratio and the solvent used for formulation modulates buoyancy and drug release from the dosage form. Commonly used polymers to develop hollow microspheres include polycarbonate, HPMC, cellulose acetate, calcium alginate, Eudragit S, chitosan and low methoxylated pectin. Several investigations have shown that the hollow microspheres are capable of floating continuously over the surface of an acidic dissolution media containing surfactant for >12 h. [9] [Figure 1] is a schematic representation of the floating microspheres.
Figure 1: Schematic representation of floating microspheres

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Advantages

Hollow microspheres offer various advantages including:

  1. Improves patient compliance by reducing dosing frequency. [15]
  2. Enhanced bioavailability despite the first-pass effect because fluctuations in plasma drug concentration is avoided; a desirable plasma drug concentration is maintained by continuous drug release. [15]
  3. Increased gastric retention time due to buoyancy. [16]
  4. Enhanced absorption of drugs, which solubilize only in the stomach. [17]
  5. Controlled drug release for a prolonged period. [16]
  6. Site-specific drug delivery to stomach can be achieved. [16]
  7. Avoidance of gastric irritation due to sustained release effect. [17]
  8. Better therapeutic effect of short half-life drugs can be achieved. [18]


Limitations

Although hollow microspheres have a number of potential advantages, their use can be limited due to the following:

  1. High level of fluids in the stomach is required for the hollow microspheres to float and work efficiently. [4]
  2. The dosage form should be administered with a full glass of water (200-250 ml). [19]
  3. Not suitable for drugs having solubility or stability problem in gastric fluids. [19]
  4. The drugs that undergo first-pass metabolism (nifedipine, propranolol, etc.) are not suitable candidates. [5]
  5. Irritant drugs to the gastric mucosa are not suitable for gastroretentive systems. [19]



   Techniques for Preparation of Hollow Microspheres Top


Various methods have been developed for the preparation of hollow microspheres. These include solvent evaporation, emulsion solvent diffusion, spray drying and miscellaneous methods. These techniques are discussed in detail in the following section.

Solvent evaporation method

Solvent evaporation technique is widely employed to obtain the controlled release of drug. In this method, the drug and polymer are dissolved in an organic phase (usually methylene chloride) and dispersed in an excess amount of aqueous continuous phase, with the aid of an agitator to form an emulsion [Figure 2]. Depending upon the hydrophilicity or the hydrophobicity of drugs, different methods are used to prepare microspheres by solvent evaporation technique [Table 1]. The oil-in-water method is frequently utilized for insoluble or poorly water-soluble drugs, whereas for hydrophilic drugs, this method is inappropriate due to dissolution and extensive loss of drug. Hence, for incorporation of hydrophilic drugs water in oil in water double emulsion method, oil in water co-solvent method and oil in oil non-aqueous solvent evaporation method can be employed. [20]
Figure 2: Schematic representation of solvent evaporation method

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Table 1: Various hollow microspheres prepared by solvent evaporation method

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Solvent evaporation is the simplest method for fabrication of microspheres where process can be controlled easily and the formed microspheres show good product yield and high encapsulation efficiency. [21] However, the limitation remains that the rate of solvent removal may affect the physicochemical properties of formed hollow microspheres and it requires additional processing for removal of residual solvent. [Table 1] lists the various hollow microspheres prepared by this method.

Emulsion solvent diffusion method

Kawashima et al. proposed hollow microspheres (so-called "microballoons") prepared by novel emulsion solvent diffusion method based on enteric acrylic polymers containing the drug in the polymeric shell. [9],[40] The preparation method and mechanism of microballoon formation is schematically illustrated in [Figure 3]. Typically, the method involves dispersion of solution of polymer and drug in a mixture of dichloromethane and ethanol into an agitated aqueous solution of surfactants. The ethanol rapidly partitions into the external aqueous phase and the polymer precipitates around dichloromethane droplets. The subsequent evaporation of the entrapped dichloromethane leads to the formation of internal cavities within the microspheres. [40],[41] The major advantages of emulsion solvent diffusion method include uniform and narrow size distribution of formed microspheres and the high efficiency of the process. However, it is relatively complex process, which cannot be controlled easily. [Table 2] summarizes the various drugs entrapped by this method.
Figure 3: Schematic illustration of hollow microsphere formation by emulsion solvent diffusion method

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Table 2: Various hollow microspheres prepared by emulsion solvent diffusion method

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Spray drying

Spray drying is the most widely employed industrial process for particle formation and drying. It is an ideal process where the required particle size distribution, bulk density and particle shape can be obtained in a single step. [68]

In this technique polymer is first dissolved in a suitable volatile organic solvent (e.g., dichloromethane, acetone) to form a slurry. The slurry is then sprayed into the drying chamber, concentration gradient of the solute forms inside the small droplet with the highest concentration being at the droplet surface. This is because the time of the solute diffusion is longer than that of the solvent in the droplets evaporating during the drying process. Subsequently, a solid shell appears leading to the formation of microspheres. Separation of the solid products from the gases is usually accomplished by means of a cyclone separator while the traces of solvent are removed by vacuum drying and the products are saved for later use [69] [Figure 4].
Figure 4: Schematic presentation of spray drying method

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Spray drying method has advantages of being an easily controlled simple process with ease of scale-up. In addition, narrow particle size distribution and required particle size can be obtained in a single step. The limitations include that the product morphology is affected by various processing variables and the high cost of the process. [Table 3] presents the various hollow microspheres prepared by spray drying method.
Table 3: Various hollow microspheres prepared by spray drying method

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Miscellaneous

Apart from the above mentioned techniques, several modifications in the fabrication of hollow microspheres have been attempted to achieve the various objectives. Some of these approaches are summarized in [Table 4].
Table 4: Hollow microspheres prepared by miscellaneous techniques

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   In vivo Profiling of Hollow Microspheres Top


In vivo investigations are an integral part for the evaluation of hollow microspheres. Some of these studies are discussed in the following section and summarized in [Table 5].
Table 5: In-vivo evaluations of hollow microspheres

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Gamma scintigraphy

Gamma scintigraphy has become one of the most popular method to investigate the gastrointestinal performance of the product. [84] Gamma scintigraphy is a technique by which the transit of a dosage form through its intended site of delivery can be noninvasively imaged in vivo by the introduction of a radiolabelled drug formulation. The gamma radiations emitted by the incorporated radionuclide with energies between 100 and 250 KeV are captured by external detectors such as gamma cameras coupled to a sophisticated data processing system and used to quantify the formulation in vivo. [85] Radiopharmaceuticals labeled with (99 mTc) technetium are most commonly used, however, other sources of radionuclides such as (111In) indium, (175Yb) ytterbium, (68Sm) Samarium, etc., can also be employed. [86] The prime advantages of gamma scintigraphy include modest radiation exposure to the participating subjects compared with roentgenography (i.e., X-ray methods), both qualitative and quantitative observations can be recorded that are not feasible with other techniques. It also offers total non-invasiveness and in vivo evaluation of dosage forms is possible under normal physiological conditions.

Radiography

Radiography has been used for many years for the assessment of gastric transit of dosage forms throughout the GIT. It involves the inclusion of a radio-opaque material into an oral drug delivery system to evaluate its in vivo behavior by radiological procedures. [87] Its major advantages over gamma scintigraphy are the simplicity and cost. However, the major drawbacks are repeated exposure to X-rays, necessity to modify the physical state of the dosage form in order to make it radioopaque and qualitative nature of the data collected. A commonly used contrast agent for radiography is barium sulphate. [88]

Ultrasonography

Ultrasonic imaging can be employed for visualizing internal body structures. An ultrasonic image is formed when beam of very high frequency sound impulse (1.5-10 MHz) is sent into a subject and is reflected back to a varying degree depending upon the density of the medium through which it is passing. [84] It is a noninvasive and safe technique. [89] Most of the dosage forms do not have sharp acoustic mismatches across their interface with the physiological milieu, thereby limiting the use of ultrasonography for the evaluation of floating drug delivery systems. The characterization includes assessment of intragastric location of the hydrogels and interactions between gastric wall and floating microspheres during peristalsis.

Alternating current biosusceptometry

Alternate current biosusceptometry (ACB) is an innovative, non-invasive and radiation free biomagnetic technique used to evaluate floating systems in the GIT. In this technique, variation of magnetic flux from an ingested magnetic material is recorded by a set of induction coils. The material (ferrites like MgFe 2 O 3 ) does not need to be premagnetized as it is continuously magnetized by an alternating field with a frequency of 10 kHz and a magnetic field of 20G generated by the excitation coils. [90] The magnetic signals detected by the ACB sensors depend on the surface area of the detection coil, number of turns, rate of change of the magnetic flux, amount of ferromagnetic material and distance among the sensors. [91]

Magnetic resonance imaging

Magnetic resonance imaging is a noninvasive imaging technique that is based on the principle of nuclear magnetic resonance. The high spatial resolution in combination with very good contrast resolution makes MRI an admirable tool in gastrointestinal research for the analysis of gastric emptying, motility and intra gastric distribution of macronutrients and drug models. The advantages of MRI include avoidance of ionization radiation, excellent anatomical imaging, high scan volumes and use of harmless MR imaging contrast agents. However, the magnetic resonance imaging encounters the problems of acquisition time and the signal to noise ratio. In order to solve these problems different strategies can be followed. [91] Use of either paramagnetic or ferromagnetic contrast agents (ferromagnetic iron oxides) for the labeling of the delivery system is very common. A combination of materials with very different contrast properties can also be used to specifically enhance or suppress signal of fluids and tissues of interest and thus permit better delineation and study of organs. [92]

[Table 5] enlists the various in vivo investigations performed with hollow microspheres.


   Conclusion Top


The process of gastrointestinal drug absorption is highly variable. Among the drugs currently in clinical use are several narrow absorption window drugs. Drugs that possess a narrow absorption window in the upper parts of the gastrointestinal tract are ideal candidates for a gastroretentive drug delivery system as prolonging gastric retention of the dosage form extends the time for the drug absorption. In spite of extensive research conducted to develop controlled or sustained release delivery systems, very few systems have been developed, which are retained in the stomach for a long time.

A wide variety of active agents of different therapeutic functions such as anti-inflammatory, antibiotics, anti-ulcer, anti-diabetic, have been formulated into hollow microspheres with promising in vitro and in vivo results. Hollow microspheres are expected to provide an economical, safe and more bioavailable formulation for the effective management of diverse diseases. Some of the hollow microsphere-related patents have been listed in [Table 6].
Table 6: Patents for some hollow microspheres based gastroretentive drug delivery systems

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It is expected that extension of applications of imaging techniques and recently developed methods may yield a deeper insight into the mechanisms of gastroretentivity. This will ensure the successful advancements in the area of gastroretentive microspheres therapy so as to optimize the delivery of molecules in a more efficient manner. Furthermore, recent innovations in pharmaceutical investigation will surely provide real prospects for the establishment of novel and effective means in the development of this promising drug delivery system.[102]

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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