Patent Review: Use of Adsorbent Carbon Microspheres for Treatment of Irritable Bowel Syndrome

United States Patent 7,749,497 was recently issued to Ocera Therapeutics, Inc. (San Diego, CA) regarding the use of adsorbent carbon microspheres for the treatment of irritable bowel syndrome.

The patent invention primarily describes the use of adsorbent carbon microspheres for the treatment of irritable bowel syndrome and symptoms associated with it.  Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by altered bowel habits without the presence of detectable structural abnormalities. IBS is fairly common and makes up 20-50% of visits to gastroenterologists.  Most commonly, patients have abdominal pain associated with altered bowel habits that consist of constipation, diarrhea, or both. The other group consists of patients with painless diarrhea.

One embodiment disclosed herein includes a method of treating one or more symptoms of irritable bowel syndrome by  administering to the subject adsorbent carbon microspheres with a particle size of 0.01mm to about 2 mm to reduce the abdominal discomfort or pain. In one embodiment, the amount of the adsorbent carbon microspheres is sufficient to achieve at least about a 50% reduction in the number of days the subject experiences abdominal pain or discomfort.

In some of the embodiments, the adsorbent carbon microspheres have a particle size of about 0.05mm to about 0.8 mm. In some of the above embodiments, the adsorbent carbon microspheres have a specific surface area of about 700 m.sup.2/g or more as determined by a BET method. In some of the above embodiments, the adsorbent carbon microspheres have a specific surface area of about 700 m.sup.2/g to about 2500 m.sup.2/g as determined by a BET method.

Microsphere Manufacturing Process:

First, a dicyclic or tricyclic aromatic compound or a mixture thereof having a boiling point of 200.degree. C. or more is added as an additive to a pitch such as a petroleum pitch or a coal pitch. The whole is heated and mixed, and then shaped to obtain a shaped pitch. Thereafter, the shaped pitch is dispersed and granulated in hot water at 70 to 180.degree. C., with stirring, to obtain a microspherical shaped pitch. The aromatic additive is extracted and removed from the shaped pitch by a solvent having a low solubility to the pitch but a high solubility to the additive. The resulting porous pitch is oxidized by an oxidizing agent to obtain a porous pitch subject to heat infusibility. The resulting infusible porous pitch is treated at 800 to 1000.degree. C. in a gas flow such as steam or carbon dioxide gas reactive with carbon to obtain a porous carbonaceous substance.

The resulting porous carbonaceous substance is then oxidized in a temperature range of 300 to 800.degree. C., preferably 320 to 600.degree. C., in an atmosphere containing 0.1 to 50% by volume, preferably 1 to 30% by volume, particularly preferably 3 to 20% by volume, of oxygen. The substance is thereafter reduced in a temperature range of 800 to 1200.degree. C., preferably 800 to 1000.degree. C., in an atmosphere of a non-oxidizable gas to obtain the final product. More details of suitable production processes and suitable products may be found in U.S. Pat. Nos. 4,681,764 and 6,830,753 and U.S. Application Publication No. 2005/0112114, filed May 26, 2005, all of which are incorporated herein by reference in their entirety. Suitable adsorbent carbon microspheres are commercially available from Kureha Corp., and is sold in Japan under the trade name KREMEZIN.RTM. (also known as AST-120).

Administration of the Microspheres to the Patient:

For use as described herein, adsorbent carbon microspheres may be administered to the gut of a subject by any suitable means. In one embodiment, the carbon is administered orally. Formulations for oral administration may include, but are not limited to, free flowing microspheres, granules, tablets, sugar-coated tablets, capsules, suspensions, sticks, divided packages, or emulsions. In the case of capsules, gelatin capsules, or if necessary, enteric capsules may be used. The oral dosage administered to a subject may be any amount suitable to achieve the desired therapeutic result. In some embodiments, the oral dosage in the case of a human is about 1 to 20 g of the adsorbent per day.

Patent Review: Preparation of Swellable and Deformable Microspheres

United States Patent number 7,794,755 was issued on September 14, 2010, describing the process for preparation of swellable and deformable microspheres. The patent is assigned to E.I. du Pont de Nemours and cites Figuly, Mahajan, and Schiffino as inventors.

A process for producing microspheres was developed that provides microspheres with new combined properties of high density, low fracture, high swell capacity, rapid swell, and deformability following swell. The process is reliable and high yielding, and makes use of a low temperature azo initiator and a small molecule chlorinated solvent as the organic phase. The microsphere preparation made using the process is particularly useful in medical treatments such as embolization.

The patent describes a need for microspheres with properties that are advantageous for many types of applications, including medical applications. Microspheres with high density, yet a large capacity to swell in an aqueous environment, would be useful for absorption applications such as small-scale spill control and for delivery applications in which they would carry and release active ingredients such as fertilizers, herbicides, pesticides, cosmetics, shampoos, and medications. Microspheres with additional properties of durability and deformability would provide a valuable material for introduction into animals, including humans, for applications such as tissue augmentation, void filling, wound treatment, and embolization. Tissue augmentation involves introduction of materials in a collapsed area to provide a filling function, such as the treatment of scars or wrinkles. Void filling involves introduction of materials into an empty space, such as one created by removal of a tissue mass. Wound treatment involves introduction of materials to stop bleeding, provide padding, deliver medication, and absorb fluids. Such materials are useful especially in emergency situations including accidents and military operations. Embolization treatment involves the introduction of a material into the vasculature in order to block the blood flow in a particular region, and may be used to treat non-cancerous tumors, such as uterine fibroids, and cancerous tumors, as well as to control bleeding caused by conditions such as stomach ulcers, aneurysms, and injury. Blockage may be desired in the case of arteriovenous malformation (AVM), where abnormal connections occur between arteries and veins. Additionally, blockage may be desired for pre-surgical control of blood flow.

The patented process makes use of a water soluble, low temperature-active azo initiator in an aqueous solution of monomer, crosslinking agent, and emulsifier. A chlorinated organic medium is used in forming a suspension with the aqueous solution. The aqueous solution and organic medium both additionally include protecting colloids. The aqueous solution and organic medium, as well as the mixture of the two, are initially held below the initiation temperature of the azo initiator. The organic medium, which may comprise a chloroform and methylene chloride mixture, should have a high enough boiling temperature that the aqueous soluble azo initiator can be activated to cause polymerization producing microspheres.

A prevalence of the microspheres are in the size range of about 25 to about 250 microns in diameter, as seen when analyzing a small sample size of microspheres. A heterogeneous size mixture of microspheres may be separated into microsphere samples of specific size ranges, if desired, for specific applications. Microspheres may be separated by methods such as fluidized bed separation and custom sieving, also called screen filtering.

The swell capacity (amount of water uptake) of microspheres prepared by the described process may vary depending on the amount of crosslinking agent added to the first solution. For example, crosslinking agent may be added in such an amount as to impart a swell capacity to the microspheres of about 50 grams of water per gram of microspheres, an amount to impart a swell capacity of about 70 grams per gram of microspheres, and alternatively an amount to impart a swell capacity of about 100 grams per gram of microspheres.

An additional attribute of the microspheres prepared by the present process is the capacity to deform following swell. When placed under pressure, the swelled microspheres do not maintain their substantially spherical shape, but compress in the axis of the pressure and expand in the axis that is perpendicular to the pressure. Thus environmental factors, such as pressure of a flowing medium or from the walls of an enclosing container, may cause deformation of the microspheres. In addition, pressure of individual microspheres next to each other may cause deformation. This ability to deform is thought to be imparted and enhanced through the closed cell void structure of the microspheres.

This ability to deform allows the microspheres to take on a shape of a containing space, and to fill that space. Additionally, deformed microspheres have increased surface area contact with each other, as compared to the contact area between spherical beads. The increased surface area contact between the deformed microspheres provides a more compact structure than is achievable with non-deforming spherical microspheres. This compact structure provides high resistance to penetration. The deformability is highly desirable in some applications such as in embolization treatment, where the deformed, compact microspheres may provide strong blockage at target vascular sites.

ParaMagnetic Microspheres

Paramagnetic microspheres have the ability to increase in magnetization with an applied magnetic field and loose their magnetism when the field is removed. Neither hysteresis nor residual magnetization is observed and that provides the end use two very practical advantages:

• When the filed is removed, the microspheres demagnetize and re-disperse easily. This property allows efficient washing steps, low background and good reproducibility.
• The behavior of the microspheres is always the same whatever the magnetization cycles may be. Such behavior is a key point for automated instrument.

106-125um Magnetic Microspheres

Recently black paramagnetic microspheres have been produced in larger sizes of 10 micron to 1mm (1000um) and in dry form enabling scientists to leverage the benefits of paramagnetic particles in new applications. These highly spherical polyethylene microspheres offer the flow-ability of standard microspheres, with the ability to be separated from other materials for re-use and cleanup.

One use of paramagnetic microspheres as large as 1mm in diameter to simulate salmon eggs, Scientists are able to place them in a natural habitat, observe how they move with the water currents and then use their magnetic properties to clean them up.

SuperParamagnetic microspheres, sometimes just called magnetic microspheres or paramagnetic microspheres have become widely used in the life sciences industry (<10um diameters) for applications such as:

• Solid Phase Immunoassays
• Bacteria Detection
• High Throughput screening
• Rapid Tests
• Cell Sorting
• Biosensors
• Nucleic Acids Technology
• Microfluidics¹

Super paramagnetic microspheres used in the life science industry are supplied in solution form.

1. Merck Estapor Super Paramagnetic Microspheres Brochure

Technical Characteristics of PMMA Microspheres

PMMA microspheres - Cospheric LLC

PMMA micropsheres or polymethylmethacrylate microspheres are often referred as acrylic microspheres.  PMMA polymer is an amorphous, transparent and colorless thermoplastic that is hard and stiff. It has good abrasion and UV resistance and excellent optical clarity. It has somewhat poor solvent resistance. PMMA spheres are soluble in organic solvents such as acetone, benzene, or halogenated hydrocarbons. Though flammable, PMMA material has low smoke emission.

Poly(methyl methacrylate) or PMMA is less hydrophobic than polystyrene and reported to show reduced nonspecific protein and peptide binding. The density of these beads, 1.19 g/cc, is considerably heavier than polystyrene particles, allowing more rapid separation and making them easier to concentrate by centrifugation. The particles typically have a hydrophilic anionic surface with refractive index of 1.48.

PMMA micropsheres have good biocompatibility which allows the particles to be used in many medical and biochemical applications. Diameter and monodispersity specifications for the micropsheres are dictated by the requirements of each application.

PMMA micropsheres are used in such a wide variety of industries as investigations in the colloidal crystal field, toners for copying machines, biomedical devices and injectable dermal fillers.

Research quantities of PMMA microspheres can be obtained from several suppliers depending on the desired particle size.

Bangs Labs offers PMMA microspheres 0.5 micron – 5 micron in diameter. Cospheric LLC sells research samples of PMMA spheres in several tight size ranges from 10 micron to 150 micron. Goodfellow offers polymethylmethacrylate spheres in two diameters of 1.5mm and 3.18mm.

Below is some detailed technical information on material properties of PMMA:
(source: Goodfellow)

Electrical Properties

Dielectric constant @1MHz     2.6
Dielectric strength ( kV mm-1 )      15
Dissipation factor @ 1MHz      0.014
Surface resistivity ( Ohm/sq )      1014
Volume resistivity ( Ohmcm )      2-14 x 10¹⁵

Mechanical Properties

Elongation at break ( % )      2.5-4
Hardness – Rockwell M     92-100
Izod impact strength ( J m-1 )      16-32
Poisson’s ratio      0.35 – 0.4
Tensile modulus ( GPa )      2.4-3.3
Tensile strength ( MPa )      80

Physical Properties

Abbe number      57.2
Density ( g cm-3 )      1.19
Flammability      HB
Limiting oxygen index ( % )      17-20
Radiation resistance      Fair
Refractive index      1.49
Resistance to Ultra-violet      Good
Water absorption – over 24 hours ( % )      0.2

Thermal Properties

Coefficient of thermal expansion ( x10-6 K-1 )       70-77
Heat-deflection temperature – 0.45MPa ( C )      105
Heat-deflection temperature – 1.8MPa ( C )     95
Lower working temperature ( C )      -40
Specific heat ( J K-1 kg-1 )        1400 – 1500
Thermal conductivity @23C ( W m-1 K-1 )      0.17-0.19
Upper working temperature ( C )      50 to 90

Cosmetic Applications of Injectable Polymer Microspheres

Polymer microspheres, in particular injectable polymer particles with a diameter in the range of 30−300 μm, are becoming widely used as a biomaterial in different clinical fields, such as cosmetic surgery, reconstructive surgery, and urology.  Injectable skin fillers offer many benefits in cosmetic dermatology, allowing new forms of facial rejuvenation and wrinkle treatment without surgery. Injectable skin and wrinkle fillers are used to increase tissue volume, reduce wrinkles, and improve skin’s overall contour.

According to The American Society for Aesthetic Plastic Surgery,  two formulations of fillers that are based on microsphere technology are FDA approved for use, differing in design and expected longevity of results.  These injectable microspheres products are used for volume replacement and for deep facial wrinkles (such as the nasolabial folds.) They are not approved for use in the lips.

One of cosmetic dermatology products using injectable microspheres is ArteFill® – a new breed of dermal filler that offers longer lasting results than other cosmetic filler injections. ArteFill® (known as Artecoll® outside of the United States) is made of polymethylmethacrylate (PMMA) microspheres (miniature beads) that are suspended in bovine collagen. Tiny microspheres are made of non-resorbable polymethylmethacrylate – a biocompatable compound that has been used for years.  PMMA has been used since the early 1930s in such common procedures as dental prostheses, eye lenses, bone repair, orthopedics and in pacemakers.  PMMA microspheres are well tolerated by human tissue (no rejection). Continue reading “Cosmetic Applications of Injectable Polymer Microspheres” »