Gelucires : Pharmaceutical Applications

By nrjadhav20 - 08/27/2008

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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

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

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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

"Gelucires : Pharmaceutical Applications" indeed a good article

Submitted by Lakshya Untwal on Thu, 08/28/2008 - 15:08.

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.

hello

Submitted by madhaviblr on Wed, 08/27/2008 - 05:55.

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