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Pullulan in Pharmaceutical

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Pullulan in Pharmaceuticals

Vinay Kumar SinghAbout Author
Vinay Kumar Singh.  
Kumar Organic Products Research Centre Pvt. Ltd., Bengaluru

Pullulan is a linear glucosic polysaccharide produced by the polymorphic fungus Aureobasidium pullulans, which has long been applied for various applications from Pharmaceutical & food additives to environmental remediation agents.

Pullulan possesses some distinct properties such as excellent transparent film–forming ability, moisture absorptivity, water solubility, non-toxicity, and adhesivity. These properties allow pullulan to find potential applications in various industries such as pharmaceuticals, cosmetics, food, and health care.

Origin of pullulan  occurred  6-7  decades  earlier  i.e.  in 1950s. Aureobasidium pullulans was first described as Dematium pullulans by De Bary. Bernier was the first to isolate pullulan form  Aureobasidium  pullulans  in  1958.  Bender et al studied the novel polysaccharides in1959  and named it  pullulan. In 1960s, the basic structure of pullulan was  resolved. They discovered the enzyme maltotriose. Thus, pullulan is viewed  as  α-(1→6)  linked  polymer  of  maltotriose subunits. Cately  and  his  coworkers  established  the  occurrence of randomly distributed maltotetraose. pullulanase,  which  hydrolyses  α-(1→6)  linkages  in  pullulan  and  converts  to  Pullulan  has  the  safe  history  of  use  in  Japan  as  a  food  ingredient  and  as  pharmaceutical bulking agent. The main use of  pullulan has  been as  a glazing  agent having oxygen barrier properties . It has Generally Regarded As Safe  (GRAS) status in US for a wide range of applications.  Human volunteer studies  have only reported the abdominal fullness at doses of 10 g pullulan per day with some mild gastrointestinal symptoms at higher doses. Pullulan is accepted for use as an excipient in pharmaceutical tablets and is listed in the Japanese Standards for Ingredients for drugs. The  commercial  production  of  pullulan  began  in  1976  by  the  Hayashibra  Company, in Okayama, Japan. Pullulan production was  an  outgrowth  of  starch syrup production, noted in 1883.  Pullulan films were commercialized by  Hayashibara in 1982. 

Pullulan Capsules are completely natural vegetable capsules. It is 100% natural and it does not include any identifiable taste. People who are hesitating to take the gelatin can easily take this substitute for their health. In coatings it replaces gelatin. As an edible, mostly tasteless polymer, the chief commercial use of pullulan is in the manufacture of edible films that are used in various breath freshener or oral hygiene products such as Listerine Cool Mint of Johnson and Johnson (USA) and Meltz Super Thin Mints of Avery Bio-Tech Private India Ltd.  In the United States, the FDA approved pullulan as safe in 2002. In the European Union, it was recently approved as a food additive (E 1204) for use in capsules, tablets, and films under directive 2006/52/EC. Its use in the food industry is also permitted in several Asian countries, in Russia, and in some South American countries. An advantage of the use of pullulan as a packaging material is its biodegradation, thermal stability, elasticity, and high barrier properties toward oxygen and carbon dioxide.

Moreover, pullulan-based coatings do not have any taste or aroma and are colourless and shiny. Pullulan is a tasteless and odourless white powder. The unique structure of pullulan is responsible for pullulan's high solubility in water and flexibility. The polysaccharide is insoluble in organic solvents, yet highly soluble in water. Solution of pullulan is stable over a wide range of pH and is heat resistant. It is an adhesive when dissolved in water and shows superior adhesiveness on wood compared to corn starch and modified cellulose. Pullulan readily forms a film that is edible, transparent, oil impermeable, and readily soluble in water. The compound is nontoxic, nonmutagenic, noncarcinogenic, biodegradable, and edible. All these exclusive characteristics make pullulan an ideal alternative candidate to petroleum-based polymers. Pullulan dissolves readily in water to form a stable, viscous solution that does not gel. In an atmosphere of a relative humidity of less than 70%, pullulan has an equilibrium moisture content of 10–15% but no hygroscopicity or tackiness. Pullulan resembles gum arabic in viscosity. Its solutions have a surface tension approximating that of water, 74 dyne/cm2. Pullulan solution viscosity is essentially unaffected by pH over a wide range of pH values (< 2 to > 11). It is also relatively heat stable.

Pullulan is stable in the presence of most metal ions.The viscosity shows a sharp increase in the presence of certain ions such as borate that are capable of complexing with hydroxyl groups. Even under such conditions, pullulan does not gel. A significant feature of pullulan is its high stability to sodium chloride. Heating at 100° for 6 hr in 30% sodium chloride effects no noticeable change in viscosity. Pullulan solutions impart high strength to paper or wood and adhere to inorganic substances such as glass, metal and concrete when applied thereon and dried. Pullulan begins thermal decomposition and carbonizes at 250–280°. Pullulan is susceptible to pullulanase and isopullulanase (4-alpha pullulan hydrolase), enzymes that specifically hydrolyze pullulan. Pullulan powder appropriately moistened can be molded by compression molding or extrusion molding while applying heat. Also, pullulan can be spun into fibers or filaments by wet or dry spinning. Films can be made by casting an aqueous pullulan solution on a clean and smooth surface and applying continuous drying. The film dissolves readily in warm or cold water three times faster than does PVA film. It is heat stable and does not lose its flexibility and elasticity even at temperatures of less than 0°.

Pullulan films have a low oxygen permeability of 0.5 cc/m2 • 24 h • atm at 60% relative humidity and 25°. The worldwide market for Pullulan is expected to grow at a CAGR of roughly 2.2% over the next five years, will reach 130 million US$ in 2024, from 120 million US$ in 2019. We at Kumar Organic Products limited manufacture Pollulan having trade name as Kopulan.  Kopulan is a 100% natural polysaccharide, produced by the fermentation of cane sugar (non GMO) by Marine Yeast Aureobasidium pullulans. Pullulan is potentially used as pharmaceutical coatings for tablets, pills, and granules because of its high water solubility and low moisture resistance. It also attracts great interest for the uses as predosed formulations wrapping materials for soft and hard capsule.

Pullulan can be formed into capsules. Its excellent oxygen barrier properties ensure that the shelf life of products is optimized. It is non animal origin ensures its suitability for all consumer groups.  Its distinct advantage over gelatin capsules is that almost impermeable to oxygen. Thus suitable for encapsulating even oxidation-sensitive ingredients, while there is less need for anti-oxidants. The oxygen barrier properties of pullulan offer 250 times better protection against oxidation than HPMC capsules and 9 times better than gelatin capsules. Because of non – hygroscopic properties of pullulan films, the likelihood of a potential cross linking with encapsulated substances is significantly reduced.

• PULLULAN CAPSULES are especially suitable to protect sensitive neutraceuticals like plant extracts or anti-oxidants and pharmaceutical active ingredients
• Pullulan Tablet coats : When used in a top coat, Pullulan's adhesive properties significantly increases the strength and resilience of the coating reducing damage during transport and distribution.
• Pullulan Oral Strips: Rapid dissolving dosage form (RDDFs) has become increasingly important because of their unique properties. They quickly disintegrate and dissolve, and can be administered without water, making them particularly suitable for pediatrics and geriatric patients.Film formed were transparent, clear, shiny, homogeneous & smooth. Typical strips or films will be between 10-50 mm wide, and 10-50 mm long and weigh 20-100 mg. Maximum dissolution time for Maximum dissolution time for fast dissolving films is 60 sec and thickness 20-70μm.
As Pullulan film is formed, it can be used to entrap flavors, colors and other active ingredients.  Due to its excellent oxygen barrier properties these ingredients are effectively stabilized in the film is formed.  The film can then be cut to any size. Such technology provides an innovative and ‘easy to use’ carrier and delivery system for a wide variety of ingredients. Furthermore as flavors are sealed in the film matrix such technology provides a means to deliver highly pungent materials which would otherwise need to be segregated.

Pullulan in Tissue engineering and grafting: The surface and the bulk property of any biomaterial is important as it influences the dynamic reactions that take place at tissue implant interface. These properties or the change in the property which can take place over time in-vivo, should be known  for  designing the  biomaterial  for  specific  applications and  this  can be easily done with pullulan. Na and his co-workers conjugated the pullulan with an interferon-water-soluble  low  molecular  weight  recombinant  protein  which  had both anti-viral and immunoregulatory activity. This allowed the user to preserve the biological activity of the drug while enhancing its liver accumulation.Surface modification is an utmost tool for tissue engineering purpose. The surface modification  can  be  easily  done  with  pullulan  as  it  comprises  nine  hydroxyl groups for substation reactions on the repeating unit. 

Applications of pullulan can be enhanced by grafting different chemical groups on it as it contains nine hydroxyl groups, which can be easily substituted. The weight of pullulan increases when grafting is  done. The increase in weight of pullulan after grafting clearly indicates the grafting of concerned group on to pullulan.

Pullulan as a carrier for drug delivery : Stimuli-sensitive polymer systems have been used as materials for the delivery of drug.  Gheorge et  al grafted poly(N-isopropylacrylamide-co-acrylamide) onto  the  pullulan  in  order  to  confer  their  temperature  sensitivity.  Then the remaining hydroxyl groups of the pullulan were reacted with succinic anhydride to introduce the pH-sensitive units (-COOH), resulting into the more hydrophilic nature than the native pullulan [43]. Thus, pH-sensitive pullulan microspheres can be prepared for controlled delivery of the drug.

• Liver targeting study focuses on the blood compatibility of the cationic
Liver targeting study focuses on the blood compatibility of the cationic pullulan,  physico-chemical  characterization,  uptake  of  nanocomplex  by hapatocytes and in-vitro transfection. Liver targeting can be achieved by using drug loaded pullulan. Xi and his co-workers studied the liver binding affinity  of  the  modified  pullulan in-vitro  in  hepatocytes and  in-vivo  in mice.
• Pullulan can be used for tumour cell targeting. Scomparin et al designed

Pullulan can be used for tumour cell targeting. Scomparin et al designed two  new  anti-cancer  polymers  for  tumour  cell  targeting.  Pullulan  was derivatized with either  doxorubicin or doxorubicin and folic  acid. Then, pullulan  was  activated  by  periodate  oxidation  and  functionalized  by reductive  conjugation  cysteamine  and  1.9  kDa  ammonium polyethyleneglycol  [PEG  (NH2)].  This  study  suggests  that doxorubicin-pullulan bioconjugates possess suitable properties for passive tumour targeting while folic acid conjugate of pullulan has a limited effect on selective cell uptake.

Application of pullulan to the gene delivery is being explored. Gene therapy using viruses have been performed, but the major drawback of using viruses is that they are immunogenic, disease causing and can be hazardous to health. Pullulan being non-toxic  and  biocompatible  is  investigated  for  gene  delivery  application. Hosseinkhani et al mixed the pullulan derivative with a plasmid DNA in aqueous solution containing zinc ions to obtain the conjugate of pullulan derivative with plasmid DNA with Zn2+ coordination.

Following are recent advances of pullulan.
Fast disintegrating tablet using pullulan as diluent: Tablet hardess was found to increase without increasing the disintegrating time with high concentration of pullulan.

Pullulan /Silver Nanoparticles composite nanospheres using electrospray techniques for antibacterial application: Controlled spherical structure by controlling the concentration of pullulan, enhanced antibacterial activity Self assembled nanogels of hydrophobized pullulan : Size stability, micelles showed long term colloidal stability with nearly negative neutral charge.

Pullulan acetate coated magnetic nanoparticles for hyperthermia:Nanoparticles have high magnetite content, good biocompatibility, good heating property in magnetic field, and have evident cellular uptake by tumor cells.
Rapid dissolving films of cetirizine hydrochloride using pullulan as a film forming agent: Pullulan acted as rapid film forming agent.

Conclusion :
Pullulan has gained a lot of attention in the past  few decades due to its  unique properties.  Pullulan  is  an  edible bio-polysaccharide  with  numerous applications  in  the  field  of Pharmaceutical  industries.  The  unique property of pullulan  is due to its glycosidic  linkage. Pullulan is synthesized by fermentation  of  cane sugar,  beet  molasses,  agro-industrial  waste.
Pullulan can be easily derivatized  by means  of chemical  reaction. Pullulan is used as pharmaceutical coatings for tablets, pills, and granules and also used as capsule.Pullulan has important  application in  the  field of  biomedical and  pharmaceutical  field  viz., tissue engineering & grafting. Pullulan has been used for liver and tumour target delivery of drug. Pullulan has the application in the field of targeting of drug to liver  and  cancer  cells. Thus Pullulan (Kopulan)  has  occupied  a  niche  area  in Pharmaceutical field.