Gelucires : Pharmaceutical Applications

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The major problems affecting design of any dosage form are related with the solubility and stability of drug substances.

And hence to solve these problems carriers like polyethylene glycol (PEG), polyvinyl pyrollidone (PVP), poloxamers, polyols, organic acid and hydrotropes helping the dissolution enhancement of poorly soluble drugs are used.1

But now a days new type of excipients which are polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol (PEG) called as gelucire are used. They are a group of inert semi-solid waxy amphiphilic excipients, which are surface active in nature and disperse or solubilize in aqueous media forming micelles, microscopic globules or vesicles. They have been widely studied as controlled release matrices as well as for improvement of physicochemical properties of drug. They are identified with respect to their melting point and HLB value 2.

Introduction

The major problems affecting design of any dosage form are related with the solubility and stability of drug substances. And hence to solve these problems carriers like polyethylene glycol (PEG), polyvinyl pyrollidone (PVP), poloxamers, polyols, organic acid and hydrotropes helping the dissolution enhancement of poorly soluble drugs are used. 1

But now a days new type of excipients which are polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol (PEG) called as gelucire are used. They are a group of inert semi-solid waxy amphiphilic excipients, which are surface active in nature and disperse or solubilize in aqueous media forming micelles, microscopic globules or vesicles. They have been widely studied as controlled release matrices as well as for improvement of physicochemical properties of drug. They are identified with respect to their melting point and HLB value 2.

Physico-chemical Properties of Gelucire

  • Gelucire are polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol (PEG). Each component presents different affinity for water and act as surfactant and co surfactant. Di- and triglycerides are lipophilic in nature 2
  • Certain gelucires are produced by the reaction of hydrogenated palm kernel oil and polyethylene glycol, PEG 33 (Gelucire 44/14). It contains PEG 33 esters (mainly PEG mono- and dilaurate, i.e; esters of PEG with C12 chains either at one end only or at both ends), glycerides (mainly mono-, di- and trilaurin, i.e. the triglyceride with C12 chains), unreacted PEG 33, and a small amount of glycerol
  • The wide varieties of gelucire are characterized by a wide range of melting points from about 33 oC to about 64 oC and most commonly from about 35 oC to about 55 oC, and by a variety of HLB values of from about 1 to about 14, most commonly from about 7 to about 14. 3

Depending on the chemical composition of gelucire they are used for different purposes. Gelucire 44/14 possesses surfactant and self-emulsifying properties and can be used as meltable binder by melt granulation of poorly water-soluble active substance. In contact with aqueous fluids it forms a fine emulsion, solubilizes the active substance and hence increases its oral bioavailability. The hydrophilic property of gelucire is useful in the dissolution enhancement as well as in control release formulation 4

  • Low HLB gelucire can be used to reduce the dissolution rate of drugs 5

  • High HLB gelucire can be used for faster release of drugs 6

  • In the designation of gelucire names, for example, Gelucire 54/02, 54 indicates melting point and 02 indicates its HLB value.

  • Types of Gelucire 7

    Type

    Chemical nature

    Uses

    33/01

    Glycerol esters of sat. C8-C18 fatty acids

    Excipient, carrier, vehicle and antioxidant

    37/02

    Saturated polyglycolized glycerides

    Excipient

    39/01

    Glycerol esters of saturated C12-C18 fatty acids

    Excipient, vehicle, consistency building agent, fatting agent, antioxidant

    43/01

    Glycerol esters of saturated C12-C18 fatty acids

    Excipient, vehicle, consistency building and fatting agent

    44/14

    PEG-32 glyceryl laurate EP

    Excipient, solubilizer, emulsifier, bioavailability enhancer for capsule formulations

    50/02

    Saturated polyglycolized glycerides

    Excipient

     

    50/13

    PEG-32 glyceryl palmitostearate

    Excipient, bioavailability enhancer and controlled-release agent for hard gelatin capsule formulations

    53/10

    PEG-32 glyceryl stearate

    Excipient

    62/02

    Saturated polyglycolized glycerides

    Waxy carrier for melt processing technique

    Advantages of Gelucire

    The lipidic materials like Gelucire are considered as an alternative to the polymers used in the sustained release formulation because of some advantages like;

    • The have low melt viscosity
    • Absence of toxic impurities such as residual monomer catalysts and initiators
    • Potential biocompatibility
    • Biodegradability and prevention of gastric irritation by forming a coat around the gastric irritant
    • Applications of Gelucire in pharmaceutical formulations

    Name of Drug

    Difficulty with drug

    Type of Gelucire

    Method Used

    Application of Gelucire

    Biophosphonates

    (Risedronate sodium)8

    Poor bioavailability and Gastric Irritation

    39/01

    Floating matrix by using melt solidification

    Sustained drug release, reduced gastric irritation and improved bioavailability

    Diltiazem HCl9

    High water-solubility

    43/01

    Multiple-unit floating drug delivery system

    Effective carrier for design of a multi-unit floating drug delivery system

    Theophylline 10

    High dissolution

    50/02 & 55/18

    Spheres obtained by extrusion-spheronization of matrix granulations

    Hydrophobic Gelucire 50/02 act as an inert matrix and released theophylline very slowly compared with Gelucire 55/18, which acted as a hydrophilic matrix.

    Carbamazepine formulations11

    The frequency of dosing in chronic therapy and the variability in drug plasma concentration

    50/13

    Semisolid matrix filling capsule technology

    Reduction in frequency of dosing in chronic therapy by extended release formulation and decrease in the variability in drug plasma concentration.

    Microspheres of carbamazepine12

    Improvement in dissolution and bioavailability

    50/13

    Spray-congealing technique using the ultrasonic atomizer

    Improved dissolution rate and bioavailability

    Lysozyme incorporated into glyceryl palmitostearate (GPS) pellets13

     

    Improvement in drug release and bioavailability

    50/13

    Pellets prepared by compression and melting

    Melted matrices increased the percentage of lysozyme released in vitro. and controlled release of proteins

    Nicotine 14

    Colon specific delivery

    50/13

    Capsule containing drug and carbomer in Gelucire

    Slowed linear release over 6 hrs

    Low molecular weight heparin (LMWH) as well as unfractionated heparin (UFH)15

     

    Very poor intestinal absorption.

    44/14

    Oral formulation

    Improved absorption from intestine

    Propranolol 16

    To regulate release from pellets

    50/02

    Direct pelletization technique in fluidized-bed rotary granulator

    Drug release was adjusted by varying the ratio of Gelucire and other polymer as well as thickness of the coat

    Caffeine17

    To study effect of drug on solid structure and its release mechanism

    50/13

    Matrix of the drug

    Drug influences release mechanism in Gelucire matrix systems.

    Piroxicam 18

    Poor solubility

    44/14

    Semi-solid dispersion capsules

    Increased solubility and rapid onset of action in painful conditions

    Tocopherol19

    Poor bioavailability

    44/14

    Matrix of drug with Gelucire

    two-fold increase in total tocopherol absorption compared to the commercial preparation

    Diazepam 20

    Poor water-solubility

    50/13

    Melt agglomeration

    Faster dissolution rates.

    phenytoin sodium 21

    Improvement in release profile

    33/01 &

    44/14

    Semisolid lipophilic matrix filled in hard gelatin capsules

     

     

    Lipophilic and amphiphilic gelucires showed the best release profiles than marketed formulation

    To obtain 400 m spheroids 22

    To improve patient compliance particularly in the case of children and old people

    Gelucire

    50/02

    Extrusion-spheronization through a 400 m orifice

    Precirol and Gelucire

    50-02 wetted with a sodium lauryl sulfate solution show plastic flow and which help in forming 400m spheroids

    Bovine serum albumin

    (BSA) 23

    To improve the release characteristic of protein

    50/02

    Solvent-free microparticles obtained by supercritical (SC) fluid-based coating technology

    Prolonged release of the BSA

    Naproxen, Ketoprofen and Indomethacin 24

    Investigate changes in drug dissolution on storage of ternary solid-dispersion granules

    50/13

    Hot-melt granulation

    Ostwald ripening determined drug dissolution in solid-dispersion granules upon storage.

    Potassium chloride 25

     

    To achive sustained release of KCl

    Different kinds of Gelucire

    Semi-solid matrices

    Incorporation of higher the melting point Gelucire reduced the release rate of the KCl

    Sterol & Stanol Compounds26

     

    To develop Dispersible Oral formulation

    44/14 & 50/13

    Matrix system

     

    Gelucire acted as a good carrier in this formulation.

    Nifedipine 27

    To improve Release characteristic

    50/10

    Matrix formulation

    Controlled release of Nifedipine from matrices

    Oral Dosage Form Drug + Gelucire + Polymer Sumikagel28

    Formulation with improved dissolution pattern

    Gelucire and polymer Sumikagel.

    Solid dispersion

    Plays a role of an erodible polymer matrix with a low rate of erosion

    Hydrophilic Macromolecules- Fluorescein Isothiocyanate-Dextran 29

    Poor absorption

    50/13

    Palmitoyl glycol chitosan Hydrogels prepared by freeze-drying

    Controlled release was seen and absorption was improved

    Nifedipine 30

    Poor solubility

    50/13

    Polymer matrix consisting of Pluronic and Gelucire

    Nifedipine is released faster from the solid dispersion than from the pure crystalline drug of the same particle size.

    Meloxicam 31

    Poor Solubility, Dissolution And Absorption Rates

    44/14

    Amphiphilic matrix

    Improved Solubility, Dissolution And Absorption Rates

    Halofantrine 32

    Poor aqueous solubility and poor bioavailability in commercial tablets

    50/13

    Solid dispersion

    Improved aqueous solubility and

    bioavailability than commercial tablets

    Antiviral agent UC-781 33

    Poor solubility

    44/14

    Solid Dispersion

    Solubility/dissolution rate was enhanced

    Sodium salicylate 34

    To achieve control release

    50/13

    Spherical oral devices

    Control release was achieved

    Salbutamol sulfate 35

    Influence of aging on the release of drug

    35/10, 48/09 & 46/07

     

    Oral formulations (lipid matrices)

    G35/10 –fast release and show decreased dissolution.

    G48/09- slow release and show decreased dissolution

    G46/07- slowest release with no alteration in dissolution

    Naloxone hydrochloride 36

    To formulate sustain release formulation by using Gelucire

    53/10, 50/13 & 42/12

    Matrix form of dosage form.

    G53/10-12hr sustain release

    G50/13&42/12 in the ratio 80:20 to 95:5-6 to 9 hr sustain release

    17-Estradiol hemihyadrate 37

    Poorly water-soluble

    44/14

    Solid dispersion

    Increase in dissolution rate

    Proxyphylline 38

    Comparative drug release using two different Gelucire in formulation

    50/02 & 50/13

    Hard gelatin capsules.

    Gelucire with extreme HLB and viscosities, will give an optimal drug release

    DMP 323-HIV protease inhibitor 39

    Poor bioavailability

    44/14

    Semi solid formulation.

    Bioavailability was increased to 50%

    Pesticide carbaryl 40

    To reduce environmental impact produced by this agent

    54/02

    Microspheres prepared by hydrophobic congealable disperse-phase method

    The controlled-release system has a lower potential risk for groundwater contamination

     

    Gelucire 41

    Effects of storing in different Gelucire

    43/01,50/02, 50/13 &55/18

    Differential scanning calorimetry (DSC)

    Containing a high proportion of PEG stearates showed more changes when stored at elevated humidities than those of higher proportion of glycerides.

    Albendazole sulphoxide 42

    Evaluate its absorption and so as to improve systemic infection chemotherapy

    44/14

    A lipidic matrix

    Lipidic matrix does not improve the physicochemical properties of albendazole sulphoxide powder

    Nifedipine 43

    Chemical stability of nifedipine sustained release dosage forms prepared with Gelucire 53/10

    53/10

    Sustained release tablet

    It was found that nifedipine in the sustained release formulations was chemically stable against the effects of temperature and humidity

    Etofylline, Diprophylline and Proxyphylline Suspension 44

    Rheological study of suspension using different Gelucire composition

    Different types of Gelucires

    Suspension preparation

    These rheological properties depend upon the chemical composition of Gelucires and drugs used

    Amoxicillin 45

    To achieve sustain release pattern of drug

    64/02

    Formulations prepared by fluid-bed coating of direct acting granules

    Adequate sustained-release properties in vitro.

    Triamterene or Temazepam 46

    To study effect solidification of PEG and Gelucire drugs to liquid-fill in hard gelatin capsules.

    44/14

    Solid Dispersion

    Reducing the rate of solidification could lead to incomplete solidification, giving products that are liable to change on storage.

    Chlorpheniramine maleate 47

    Poor drug release

    50/02

    Spheres prepared by the extruder/marumerizer

    Increased drug release

    series of dispersions containing theophylline 48

    To study dissolution, erosion and swelling profiles of the drug dispersions

    43/01, 54/02, 50/02, 50/13 &55/18

    Solid dispersions

    G43/01 and 54/02- release by simple diffusion

    G55/18- diffusion and erosion

    G50/13- erosion

    G50/02 - swelling & release by diffusion

    Simvastatin 49

    Poor bioavailability

    44/14

    Semi-solid formulation

    Increased bioavalibility

    Hydrochlorothiazide 50

    Effect of physical and chemical properties on release

    50/02 & 50/13

    Matrix preparation

    G50/02- No effect on drug release.

    G50/13- increased drug release

    Insulin 51

    Poor pharmacological activity

    50/22 & 44/14

    Gels of insulin Gelucire

    Resulted in mean increase pharmacological activity of about 23 and 24%, respectively

    Novel Antiviral Agent, PG301029 52

    Very poor aqueous solubility but also degrades rapidly

    in water

    44/14

    Soft elastic capsules

    Solves the stability, solubility, and

    bioavailability problems

    Etoricoxib 53

    Poor aqueous solubility

    50/13

    Solid Dispersions Using

    Lipid Carriers by Spray Drying Technique

    Increase in the aqueous solubility

    Rofecoxib 54

    Poor aqueous solubility

    44/14

    Solid dispersions

    Enhanced the solubility and dissolution characteristics

    of drug

    Diclofenac salts 55

    Poor dissolution rate.

    50/13

    Solid dispersions

    Improved dissolution rate and solubility of drug

    Glibenclamide 56

    Poor dissolution rate and in turn bioavailability

    50/13

    Solid dispersions

    Improved solubility and bioavailability

    Ibuprofen 57

     

    Poor drug release

    62/02

    Preparation of Beads by melt solubilization technique

     

    Better integrity

    and prolonged drug release by using a combination of waxes.

     

    Propranolol 58

    Poor bioavailability

    44/14

    Matrix-in-cylinder system with a HPMC-Gelucire core.

    Improved bioavailability

    Metaloenzyme, seratiopeptidase 59

    Poor oral absorption.

    43/01

    Matrix system

    Improved oral absorption.

    Theophylline 60

    Poor Drug Release

    50/02

    Lipidic matrix pellets

    Faster Drug release

    Ranitidine Hydrochloride 61

    Formulation design using Gelucire

    43/01

    Multiunit floating granules by melt granulation method

    Hydrophobic lipid Gelucire 43/01 is an effective carrier for the multiunit floating drug delivery system of highly water soluble drugs

    Praziquantel62

     

    Poor dissolution rate

    50/13

    Melt granulation and ultrasonic spray congealing

    Improved dissolution rate

    Β-Lactum Antibiotics ( Cephalexin And Cefoperazone) 63

    To study In vitro and in situ intestinal transport

    Gelucire 44/14 and Labrasol

    Dispersion of Drug, Gelucire and Labrasol

     

     

    1) Gelucire 44/14did not affect the P app and CL app of either drug.

    2) Labrasol made enhancement of the active transport of cephalexin

    Method for analysis of Gelucire Containing Formulations

    • The physical stability of drug in the matrix systems as a function of time, temperature and relative humidity can be studied.
    • Differential scanning calorimetry (DSC) & powder X-ray diffractometry (PXRD): crystallinity and polymorphic and/or pseudo-polymorphic form of drug in a matrix containing gelucire can be studied.
    • Diffuse Reflectance Infrared Fourier transform spectroscopy (DRIFTS): The nature of the interactions between drug and the constituents of the polymeric matrix
    • Hot Stage Microscopy (Thermo microscopy)
    • Hot Stage Polarizing Microscopy (HSPM)
    • Scanning Electron Microscopy (SEM)
    • Saturation solubility of formulation.

    Conclusion

    Gelucires are biocompatible polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and di esters of polyethylene glycol (PEG). By changing the chemical composition wide array of gelucires having different melting point and HLB values can be prepared. These gelucires with differing melting point, hydrophilicity and lipophilicity can be used in formulation of disperse phase systems, solubility enhancement and modified release.

    References

    1) Ahuja N., Katare OP., Singh B.; European Journal of Pharmaceutics and Biopharmaceutics, 2006

    2) Sharma DK., Joshi SB. ; Asian Journal of Pharmaceutics; 2007 , 1(1), 1-11.

    3) Sheu  MT, Hsia A. ; Chin Pharm J. 2001; 53:107-111.

    4) Chambin O., Jannin V., Drug development and Industrial pharmacy; 2005, 31(6) 527-34.

    5) Huet de Barochez, Drug development and Industrial pharmacy, 1989, 15(6&7), 1001-1020.

    6) Huet de Barochez, Drug development and Industrial pharmacy, 1989, 15(6&7), 1001-1020

    7) Chemical Manufacturers Directory of Trade Name Products (Gattefosse St priest, Cedex, France.)

    8) Chauhan B., Shimpi S., Mahadik K., Paradkar A., Acta Pharma.,2004,54(4),205-14.

    9) Chauhan B., Shimpi S., Mahadik K., Paradkar A ; AAPS PharmSciTech, 2004, 5 (3), 1-6.

    10) Montousse C., Pruvost M., Rodriguez F., Brossard C., Drug development and industrial pharmacy ; 1999, 25(1): 75-80.

    11) Galal S., El Massik MA., Abdallah OY .,Daabis NA., Drug Dev Ind Pharm; 2004, 30(8) : 817-29.

    12) Passerini N., Perissuti B., Moneghini M.; Journal of Pharmaceutical science; 2002, 91(3); 699-707.

    13) Pongjanyakakul T., Medlicott NJ., Tucker IG., International journal of pharmaceutics, 2004, 271(1-2), 53-62.

    14) Green JT, Evans BK, Rhodes J , Thomas GA , Ranshaw C , Feyerabend C, Russell, M A; British-Journal-Clinical -Pharmacology. 1999, 48(4): 485-93.

    15) M ori S. , Matsuura A. , Prasad YVR. , T akada K.; Biol. Pharm. Bull., 2004, 27(3), 418-421.

    16) Nuttanan S., Varaporn J ,Ampol M.; Powder technology ; 2004,141(3), 203-209 .

    17) Khan Nurzalina ,Craig Duncan Q. M.; Journal of control Release, 2003,93(3), 355-68.

    18)Karataş A., Yüksel N., Baykara T., Il Farmaco, 2005 60(9), 777-782.

    About Authors:

    Namdeo Jadhav

    Namdeo Jadhav
    Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy, Kolhapur-416013, Maharashtra State, India.
    For correspondence
    Email: nrjadhav18@rediffmail.com
    Phone: 91-0231-2637286
    Fax: 91-0231-2638833

    Sanjeev Gubbi

    Sanjeev Gubbi

     Hanmantrao Kadam

    Hanmantrao Kadam
    Bharati Vidyapeeth, Institute of Pharmacy, Pune, 411038, Maharashtra State, India

    Sagar Yadav

    Sagar Yadav

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    Comments

    Madhaviblr's picture

    dear mr. namdeo, mr. sanjeev, mr. hanmanth rao and mr. sagar,
    this article is very captivating because you have highlighted a key excipient being heard about in various research lines. thank you very much for the information in a nut shell. and congratulations for the nice work. it would be nice if you can paste a picture of the excipient so that we may have a better idea by actually seeing. and if possible i would like to know the chemical structure too.
    regards
    madhavi

    Madhavi Bhavaraju

    Lakshya's picture

    Dear Sir, It is always pleasure reading your articles & this one is no exception. I am very happy with the way you have put forth the topic & also the ease with which you have talked on it.
    I wish to know what made you to write about this topic & also what are the references to get recent advancements on this topic.
    Regards.